Oral formulations and lipophilic salts of methylnaltrexone

ABSTRACT

The present invention provides compositions comprising methylnaltrexone or a salt thereof, and compositions and formulations thereof, for oral administration.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/045,108, filed on Mar. 10, 2011, which claims the benefit of U.S.Provisional Application No. 61/313,018, filed Mar. 11, 2010, the entirecontents of which are hereby incorporated by reference herein.

BACKGROUND OF THE INVENTION

Opioids are widely used in treating patients with pain. Such patientsinclude those with advanced cancers and other terminal diseases and alsothose with chronic non-malignant pain and acute non-malignant pain.Opioids are narcotic medications that activate opioid receptors locatedin the central nervous system to relieve pain. Opioids, however, alsoreact with receptors outside of the central nervous system, resulting inside effects including constipation, nausea, vomiting, urinaryretention, and severe itching. Notable are the effects of opioids in thegastrointestinal (GI) tract where these drugs inhibit gastric emptyingand peristalsis in the intestines, thereby decreasing the rate ofintestinal transit and producing constipation. The use of opioids intreating pain is often limited due to these undesired side effects,which can be debilitating and often cause patients to refuse the use ofopioid analgesics.

In addition to exogenous opioid-induced side effects, studies havesuggested that endogenous opioids and opioid receptors may also affectthe gastrointestinal (GI) tract and may be involved in normal regulationof intestinal motility and mucosal transport of fluids. Thus, anabnormal physiological level of endogenous opioids and/or receptoractivity may also lead to bowel dysfunction. For example, patients whohave undergone surgical procedures, especially surgery of the abdomen,often suffer from a particular bowel dysfunction, termed post-operativeileus, that may be caused by fluctuations in natural opioid levels.Similarly, women who have recently given birth commonly suffer from postpartum ileus, which may be caused by similar fluctuations in naturalopioid levels as a result of birthing stress. Gastrointestinaldysfunction associated with post-operative or post-partum ileus cantypically last for 3 to 5 days, with some severe cases lasting more thana week. Administration of opioids to a patient after surgery to treatpain, which is now an almost universal practice, may exacerbate boweldysfunction, thereby delaying recovery of normal bowel function,prolonging hospital stays, and increasing medical care costs.

Opioid receptor antagonists, such as naloxone, naltrexone, andnalmefene, have been studied as a means of antagonizing the undesirableperipheral side effects of opioids. However, these agents not only acton peripheral opioid receptors but also on opioid receptors in thecentral nervous system, sometimes reversing the beneficial and desiredanalgesic effects of opioids or causing symptoms of opioid withdrawal.Preferable approaches for use in controlling opioid-induced side effectsinclude administration of peripheral acting opioid receptor antagoniststhat do not readily cross the blood-brain barrier.

The peripheral μ opioid receptor antagonist methylnaltrexone has beenstudied since the late 1970s. It has been used in patients to reduceopioid-induced side effects such as constipation, pruritus, nausea, andurinary retention (see, e.g., U.S. Pat. Nos. 5,972,954, 5,102,887,4,861,781, and 4,719,215; and Yuan et al., Drug and Alcohol Dependence1998, 52, 161). The dosage form of methylnaltrexone used most often inthese studies has been a solution of methylnaltrexone for intravenousinjection.

In U.S. Pat. No. 6,559,158, the dose of methylnaltrexone for treatingmethadone maintenance patients was explored. It was hypothesized in the'158 patent, based on studies of methadone maintenance patients, thatpatients taking opioids chronically would be responsive to doses ofmethylnaltrexone that were previously considered to be too low to beclinically efficacious. (Methadone maintenance patients typically havean addiction to opiates such as heroin, oxycontin, dilaudid orhydrocone. They would have a history of a stable dose of methadonetreatment for at least 30 days of greater than or equal to 30 mg/day,and more typically higher.) Low doses of methylnaltrexone wereadministered intravenously. These doses were between 0.01 and 0.37mg/kg, wherein average peak plasma levels of 162 (30-774 ng/ml) werereported. These intravenous doses in methadone maintenance patientsinduced “immediate” laxation.

Methylnaltrexone subcutaneous injection was explored and has beenclinically approved in the United States to treat opioid-inducedconstipation in patients with advanced medical illness who are receivingpalliative care. The subcutaneous injection dose found to be effectivewas 0.15 or 0.3 mg/kg. This dose did not induce “immediate” laxation,but rather induced laxation within 4 hours in a significant number ofpatients treated.

Attempts have been made to make an oral dosage form of certain opioidantagonists, including methylnaltrexone. In U.S. Pat. No. 6,419,959, anoral dosage form is constructed so as to release certain compounds “overthe whole gastrointestinal tract.” According to the '959 patent, opioidantagonists are not always suitable for administration in an immediaterelease form due to dose limiting side effects. In addition,opioid-induced constipation was believed to result from the direct andlocal effects of opioids on receptors across the entire gastrointestinaltract. To address these issues, the '959 patent suggests dosing certainopioid antagonists, including methylnaltrexone, in a controlled-releasedosage form, thereby delivering these antagonists at acceptable doseslocally across the entire gastrointestinal tract. Data respectingmethylnaltrexone specifically, however, was not reported.

In U.S. Pat. No. 6,274,591, it was demonstrated that an enteric coatedmethylnaltrexone which released substantially no methylnaltrexone in thestomach was more effective in antagonizing the oral-cecal delay causedby morphine than was an uncoated methylnaltreone. The '591 patentsuggests and claims delivering effective amounts of methylnaltrexoneusing an oral dosage that by-passes the stomach altogether. Datarespecting laxation, however, was not reported.

In U.S. Pat. No. 6,559,158, an oral dose of methylnaltrexone wasexplored for treating constipation in methadone maintenance patients(i.e., patients shown to be highly sensitive to the effects ofmethylnaltrexone). The dose of methylnaltrexone administered orally in acapsule was 0.3-3.0 mg/kg. Methylnaltrexone capsules administered tothese patients induced laxation in the several patients tested, althoughover periods of time between 1.2 and 24 hours depending on the dose. Thefastest response was seen in the four patients receiving 3.0 mg/kg(5.2+/−4.5 hours, with a range of 1.2-10 hours).

Accordingly, the need exists for bioavailable oral dosage formulationscomprising methylnaltrexone.

SUMMARY OF THE INVENTION

Capsules containing enterically coated spheroids of a formulation ofmethylnaltrexone were tested in patients suffering from opioid-inducedconstipation. The patients in this study were receiving opioids fornon-malignant pain. (They were not chronic methadone maintenancepatients.) Patients were administered 300 mg or 450 mg of entericallycoated methylnaltrexone capsules (approximately 4 mg/kg and 6 mg/kg,respectively), which were doses within the ranges reported to beeffective in the '591 patent. The average peak plasma level ofmethylnaltrexone resulting from the 300 mg dose was less than 10 ng/mLand the average peak plasma level of methylnaltrexone resulting from the450 mg dose was less than 20 ng/mL. These preparations unexpectedly werenot effective for treating opioid-induced constipation. They did notinduce laxation and did not cause more bowel movements in patientsrelative to controls. This was surprising in view of the teachings inthe art.

Based on the results of the enterically coated methylnaltrexonecapsules, it was unclear whether achieving laxation depended on the peakplasma levels of the drug, the timing of achieving the plasma levels ofthe drug, or other factors such as a local effect. Further experimentswere conducted, and as a result, the inventors turned their attention todeveloping an oral formulation containing methylnaltrexone that was notenterically coated.

Capsules containing spheroids of a formulation of methylnaltrexone, butwithout the enteric coating, were tested in patients receiving opioidsfor non-malignant pain. Doses of 150 mg, 300 mg, 450 mg, and 600 mg weretested. These doses resulted in average peak plasma levels of betweenabout 15 and 40 ng/ml. These capsules without the enteric coating didnot induce laxation and did not cause more bowel movements in thispatient population relative to controls.

Tablets containing spheroids of a formulation of methylnaltrexone,without an enteric coating, were tested in patients receiving opioidsfor non-malignant pain. Doses of 150 mg, 300 mg, 450 mg, and 600 mg weretested. These doses resulted in average peak plasma levels of betweenabout 7 and 40 ng/ml, similar to the peak plasma levels achieved withthe uncoated capsules. These tablets without an enteric coating showedactivity with statistical significance at one dose, but did notconsistently induce laxation across all doses. That there was activitywith a tablet but not a capsule would have been surprising to one ofordinary skill in the art based on the information available in theprior art.

The prior art did not make clear what would be required to create anoral methylnaltrexone effective for treating opioid induced constipationin patients receiving opioids for non-malignant pain. First, the priorart did not make clear whether achieving laxation depended on theoverall plasma levels of the drug, the peak plasma levels of the drug,or the timing of achieving the plasma levels of the drug. Second, evenif the pharmacokinetics for achieving laxation were established, theprior art did not make clear formulation methodology for predictablycontrolling the pharmacokinetics of oral methylnaltrexone, other thanvia dose alterations and coatings. Because of the desire to furtherimprove the performance of the non-enteric coated tablet, furtherformulation development studies were undertaken.

Methylnaltrexone is hydrophilic and quite soluble in aqueous solutions.The positive charge of the quaternary amine causes methylnaltrexone tobe poorly absorbed in the gastrointestinal tract. In general, less thanabout 5% of methylnaltrexone is absorbed into the bloodstream whendelivered orally.

There are many possible general approaches to increasing the absorptionof an orally administered drug. It was unknown, however, which approachmight result in an improvement of the efficacy of oral methylnaltrexone.The inventors tested tablet formulations, capsule formulations, liquidformulations, gap junction openers, Pgp inhibitors, active transportagents, oil suspensions, effervescent solutions for rapid release, andothers. Most of the approaches attempted did not improve absorption inthe laboratory models used. In fact, when tested in certain dog models,some of the approaches had the opposite of the anticipated effect, thatis, absorption was inhibited in one or more of the tested parameters.

Ion pairing has been investigated to reduce the apparent ionic charge ona molecule. The interaction between a hydrophilic, charged molecule andan amphiphilic counter ion can make the hydrophilic moleculesufficiently lipophilic to enable (or increase) solubility of themolecule in a non-aqueous solvent. Since ion pairing increasespartitioning of the molecule into an organic phase, much of the work inthis area has been directed towards extraction of ionic molecules intoorganic solvents, separation of molecules by chromatography, reaction ofhydrophilic molecules in organic solvents, and so forth. With respect todrug absorption, most of the work has been limited to delivery of a drugto the skin, eyes, nasal cavity, or vaginal cavity (see, e.g., J.Hadgraft, “Skin Deep,” European Journal of Pharmaceutics andBiopharmaceutics 58, 291-299, 2004; Quintanar-Guerrero et al.,Application of the Ion-Pair Concept to Hydrophilic Substances withSpecial Emphasis on Peptides,” Pharmaceutical Research 14, 119-127,1997). There has been only limited work reported on in the prior art forimproving the bioavailability of orally administered drugs using ionpairs.

An ion pair between the positively charged methylnaltrexone and anegatively charged moiety was postulated by the inventors to make a“pair” that is more hydrophobic than methylnaltrexone bromide andthereby enhance the absorption of methylnaltrexone in the stomach.Various ion pairs were formed using methylnaltrexone and anions. Onesuch ion pair was formed between methylnaltrexone and dodecyl (lauryl)sulfate.

It was discovered, unexpectedly, that methylnaltrexone and anamphiphilic pharmaceutically acceptable excipient, that forms an ionpair or salt with methylnaltrexone when dissolved in solution, in asolid dosage form together with a rapid-acting disintegrant (e.g., acarbon dioxide-generating disintegrant) was effective to inducelaxation.

Without wishing to be bound by any particular theory of the invention,it is believed that there is a local gastric effect and a systemiceffect, which combine to achieve laxation when using the formulationsand preparations of the invention. Such a dual effect could suggest thatlaxation can be achieved using the oral formulations of the invention atpeak plasma levels lower than those shown to be effective forsubcutaneous injection.

The present invention relates to ion pairs of methylnaltrexone and anamphiphilic pharmaceutically acceptable excipient, methods for formingsuch ion pairs, methods for selecting such ion pairs, use of such ionpairs, compositions including such ion pairs, solid oral formulations ofmethylnaltrexone and an amphiphilic pharmaceutically acceptableexcipient, including formulations containing a rapid-acting disintegrant(e.g., effervescent or carbon dioxide-producing disintegrant), as wellas methods of using such compositions and formulations thereof.

In one aspect, the present invention provides a salt of methylnaltrexoneof the formula:

wherein methylnaltrexone is the cation of the salt, and A⁻ is an anionof an amphiphilic pharmaceutically acceptable excipient. In certainembodiments, the methylnaltrexone is (R)—N-methylnaltrexone as shown inthe formula above. The amphiphilic pharmaceutically acceptable excipientis acidic. In certain embodiments, the amphiphilic pharmaceuticallyacceptable excipient has a pK_(a) of about 3 or less. For example, theamphiphilic pharmaceutically acceptable excipient may include a sulfate,sulfonate, nitrate, nitrite, phosphate, or phosphonate moiety. In oneembodiment, the pharmaceutically acceptable excipient comprises an(—OSO₃ ⁻) group. Without wishing to be bound by a particular theory,such chemical functional groups with pK_(a) values at or below about 3allow for the ion pair to remain bound together at the acidic pH foundin the stomach. This is because the conjugate base of the excipientremains deprotonated and negatively charged, and methylnaltrexone isquaternary amine that is positively charged. The pharmaceuticallyacceptable excipient also includes a hydrophobic portion. In someembodiments, the hydrophobic portion is a branched or unbranched,saturated or unsaturated, cyclic or acyclic C₄₋₃₀ aliphatic chain, whichmay be optionally substituted. In some embodiments the pharmaceuticallyacceptable excipient is, for example, a saturated or unsaturated,branched or unbranched, cyclic or acyclic C₄₋₃₀ aliphatic group that isoptionally substituted. In some embodiments it is a saturated,unbranched, acyclic, unsubstituted C₄₋₃₀ alkyl group. In someembodiments, it is a saturated, unbranched, acyclic, unsubstituted C₇₋₁₅alkyl group. In some embodiments it is a C₁₂ n-alkyl group. In someembodiments, it is dodecyl (lauryl) sulfate. Without wishing to be boundby any theory, it is believed that the aliphatic chain makes theexcipients amphiphilic and surface active in nature, which helpstransport of the ion pair through the unstirred diffusion layer liningthe inner surface of the GI tract, thus increasing availability ofmethylnaltrexone to the GI membrane for local effects on receptor sitesand/or absorption across lipophilic barriers such as the lining of theGI tract, e.g., the stomach and upper duodenum. In certain embodiments,the methylnaltrexone ion pair is a salt that is solid at roomtemperature.

According to another aspect of the invention, a composition is provided.The composition is the salt or ion pair described above. The salt or ionpair may comprise at least 2%, at least 5%, at least 10%, at least 20%,at least 30%, at least 50%, at least 75%, at least 90%, at least 95% orat least 99% of the methylnaltrexone in the composition. In someembodiments, the composition is a pharmaceutical composition.

In another aspect of the invention, a composition for oraladministration is provided. The composition includes methylnaltrexoneand an amphiphilic pharmaceutically acceptable excipient that form anion pair or salt with methylnaltrexone when dissolved in solution,thereby increasing the octanol/water partition coefficient ofmethylnaltrexone. When the composition is dissolved in an aqueoussolution, the methylnaltrexone has an apparent octanol/water partitioncoefficient of at least 0.25 in acidic conditions, and in someembodiments at a pH between 1 and 4. A pH of between 1 and 4 is used tosimulate the physiological conditions of the stomach. In certainembodiments, the apparent octanol/water partition coefficient ofmethylnaltrexone is at least 0.5, 1.0, 5.0, 10, 20, or 30 at a pHbetween 1 and 4. Typically, the pharmaceutically acceptable excipienthas a pKa of about 3 or less so that the conjugate base of theamphiphilic pharmaceutically acceptable excipient remains deprotonatedand will be noncovalently bound to the cationic methylnaltrexone underphysiological conditions found in the stomach (i.e., a solution atacidic pH).

The composition also may include a rapid-acting disintegrant, whereinthe composition dissolves within about 15 minutes in the stomach. In atleast one embodiment, at least 50% of the methylnaltrexone in thecomposition is dissolved in 15 minutes. In other embodiments, at least75%, 80%, 85%, 90%, 95%, or even 99% of the methylnaltrexone in thecomposition is dissolved in 15 minutes. In any of the forgoingembodiments, the methylnaltrexone in the composition can dissolve within10 minutes or even within 5 minutes. The dissolution of the compositionin the stomach may be simulated by in vitro studies in a dissolutionapparatus with paddles at 100 rpm in 900 ml 0.1 N HCl at 37° C. Incertain embodiments, the disintegrant is a fast-acting disintegrant. Incertain embodiments, the composition has a dissolution profilesubstantially similar to the one depicted in FIG. 2. In someembodiments, the disintegrant is an effervescent disintegrant (i.e., onethat evolves a gas). By creating gas bubbles within the composition, thecomposition is more readily broken down thereby releasingmethylnaltrexone. Effervescent disintegrants were found to beparticularly useful in aiding in the dissolution tablets containingmethylnaltrexone and dodecyl sulfate. In certain embodiments, thedisintegrant is an effervescent disintegrant that is capable ofgenerating carbon dioxide when the composition is contacted with anaqueous medium. In any of the embodiments, the effervescent disintegrantcan be a bicarbonate or carbonate. In any of the embodiments, theeffervescent disintegrant can be sodium bicarbonate.

According to another aspect of the invention, a method of preparing amethylnaltrexone formulation is provided. The method includes combininga solid pharmaceutically acceptable salt of methylnaltrexone (that isnot an ion pair of methylnaltrexone and an amphiphilic pharmaceuticallyacceptable excipient), such as methylnaltrexone bromide or iodide, witha solid pharmaceutically acceptable salt of the amphiphilic excipient(that is not the ion pair of methylnaltrexone and the amphiphilicpharmaceutically acceptable excipient) to form a mixture. The mixturemay be wet granulated. In certain embodiments, a wet granulation ofmethylnaltrexone or a pharmaceutically acceptable salt thereof, anamphiphilic pharmaceutically acceptable excipient, at least onedisintegrant, at least one binder, at least one chelating agent, atleast one wetting agent, and optionally at least one filler is preparedand formed into a solid dosage form. In certain embodiments, a wetgranulation is formed by dry blending the methylnaltrexone or apharmaceutically acceptable salt thereof, a binder, an amphiphilicpharmaceutically acceptable excipient, and optionally a disintegrant;and granulating the dry blend with a solution of a chelating agentand/or a wetting agent to form a wet granulation. The wet granulationmay be dried and milled, and the milled dried granulation blended withan additional disintegrant (e.g., sodium bicarbonate) and optionally alubricant and/or a glidant before a solid dosage form is prepared.

In some aspects, the present invention provides compositions for oraladministration comprising a salt of the cation methylnaltrexone and theanion of the amphiphilic pharmaceutically acceptable excipient (e.g.,dodecyl sulfate). In some embodiments, the compositions for oraladministration are tablet formulations. In some embodiments, thecompositions for oral administration are capsule formulations.

In general, formulations for oral administration comprisemethylnaltrexone, an amphiphilic pharmaceutically acceptable excipientas described above, and a disintegrant, and further optionally compriseone or more other components, such as, for example, binders, carriers,chelating agents, antioxidants, fillers, lubricants, wetting agents, orcombinations thereof. In any of the foregoing embodiments, oralformulations are tablet formulations. In some embodiments, the presentinvention provides a unit dosage form comprising a formulation orcomposition described herein.

The present invention also provides methods of oral administration ofmethylnaltrexone in any context in which such administration isdesirable. For example, formulations are useful for preventing,treating, or reducing the severity of side effects resulting fromadministration of opioids, including inhibition of intestinal motilityor gastrointestinal dysfunction (e.g., constipation, GI sphincterconstriction), nausea, emesis, and pruritus. The compositions andformulations are useful for administration to patients receiving acuteopioid treatment (e.g., patients suffering from post operative ileus orgastrointestinal dysfunction resulting from acute opioidadministration). Such formulations are also useful for administration tosubjects receiving chronic opioid administration (e.g., terminally illpatients receiving opioid therapy (e.g., an AIDS patient, a cancerpatient, a patient with cardiovascular disease); subjects receivingchronic opioid therapy for pain management; subjects receiving opioidtherapy for maintenance of opioid withdrawal). In some embodiments, thesubject is undergoing opioid therapy for chronic pain management. Inother embodiments, the subject is undergoing opioid therapy for acutepain management. In certain embodiments, the pain is non-malignant pain(e.g., back pain, neuropathic pain, pain associated with fibromyalgia,osteoarthritis, etc.). In certain embodiments, the pain is chronicnon-malignant pain. In certain embodiments, the pain is malignant pain.In certain embodiments, the present invention provides a methodcomprising the step of reducing one or more side effects of opioidtherapy in a subject receiving opioid treatment comprising administeringto the subject a provided tablet formulation, as described herein. Inother embodiments, the present invention provides a method for reducingone of more effects of endogenous opioid activity in a subject (e.g.,post partum ileus) comprising administering to the subject aformulation. In some embodiments the subject is not a methadonemaintenance patient. In any of the foregoing embodiments, the subjectcan be fasted or fed. In one important embodiment, the subject is fastedovernight.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the dissolution profile of methylnaltrexone tablets andcapsules in 900 ml 0.1 N HCl, at 37 degrees C., 100 rpm Paddle.

FIG. 2 shows the dissolution profile of methylnaltrexone (150 mg)tablets formulated with sodium dodecyl sulfate and an effervescentdisintegrant, sodium bicarbonate (as described in Example 5), at 37degrees C., 100 rpm Paddle, analyzed using a Cary 50 spectrophotometer.

FIG. 3 shows a plot of the time and the percentage of patients having afirst laxation response in patients with chronic malignant painadministered an (R)—N-methylnaltrexone bromide (300 mg or 450 mg) SDStablet formulation after a 10 hour fast.

FIG. 4 includes characterization data for MNTX-heptyl sulfate. FIG. 4Ais the ¹H NMR spectrum of MNTX-heptyl sulfate. FIG. 4B is an HPLCchromatogram for MNTX-heptyl sulfate. FIG. 4C is the UV spectrum ofMNTX-heptyl sulfate.

FIG. 5 includes characterization data for MNTX-dodecyl sulfate. FIG. 5Ais the ¹H NMR spectrum of MNTX-dodecyl sulfate. FIG. 5B is an HPLCchromatogram for MNTX-dodecyl sulfate. FIG. 5C is the UV spectrum ofMNTX-dodecyl sulfate.

FIG. 6 includes characterization data for MNTX-sodium laurate. FIG. 6Ais the ¹H NMR spectrum of MNTX-sodium laurate. FIG. 6B is an HPLCchromatogram for MNTX-sodium laurate. FIG. 6C is the UV spectrum ofMNTX-sodium laurate.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION Definitions

The term “aliphatic,” as used herein, includes both saturated andunsaturated, straight chain (i.e., unbranched), branched, acyclic,cyclic, or polycyclic aliphatic hydrocarbons, which are optionallysubstituted with one or more functional groups. As will be appreciatedby one of ordinary skill in the art, “aliphatic” is intended herein toinclude, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, and cycloalkynyl moieties. Thus, as used herein, the term“alkyl” includes straight, branched, and cyclic alkyl groups. Ananalogous convention applies to other generic terms such as “alkenyl,”“alkynyl,” and the like. Furthermore, as used herein, the terms “alkyl,”“alkenyl,” “alkynyl,” and the like encompass both substituted andunsubstituted groups. In certain embodiments, as used herein, “loweralkyl” is used to indicate those alkyl groups (cyclic, acyclic,substituted, unsubstituted, branched, or unbranched) having 1-6 carbonatoms.

In certain embodiments, the alkyl, alkenyl, and alkynyl groups employedin the invention contain 1-30 aliphatic carbon atoms. In certainembodiments, the alkyl, alkenyl, and alkynyl groups employed in theinvention contain 10-30 aliphatic carbon atoms. In certain embodiments,the alkyl, alkenyl, and alkynyl groups employed in the invention contain5-25 aliphatic carbon atoms. In certain embodiments, the alkyl, alkenyl,and alkynyl groups employed in the invention contain 5-20 aliphaticcarbon atoms. In certain embodiments, the alkyl, alkenyl, and alkynylgroups employed in the invention contain 10-20 aliphatic carbon atoms.In certain embodiments, the alkyl, alkenyl, and alkynyl groups employedin the invention contain 15-25 aliphatic carbon atoms. In certain otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in theinvention contain 1-10 aliphatic carbon atoms. In still otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in theinvention contain 1-6 aliphatic carbon atoms. In yet other embodiments,the alkyl, alkenyl, and alkynyl groups employed in the invention contain1-4 carbon atoms. Illustrative aliphatic groups thus include, but arenot limited to, for example, methyl, ethyl, n-propyl, isopropyl,cyclopropyl, —CH₂-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl,isobutyl, tert-butyl, cyclobutyl, —CH₂-cyclobutyl, n-pentyl, sec-pentyl,isopentyl, tert-pentyl, cyclopentyl, —CH₂-cyclopentyl, n-hexyl,sec-hexyl, cyclohexyl, —CH₂-cyclohexyl, heptyl, octyl (capryl), nonyl,decyl (capric), undecyl, dodecyl (lauryl), tridecyl, tetradecyl,hexadecyl (cetyl), heptadecyl, octadecyl (stearyl), eicosyl (arachidyl),docosyl, tetracosyl, hexacosyl, octacosyl, triacontyl moieties and thelike, which again, may bear one or more substituents.

Some examples of substituents of the above-described aliphatic moietiesinclude, but are not limited to aliphatic; heteroaliphatic; aryl;heteroaryl; arylalkyl; heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy;heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F;Cl; Br; I; —OH; —NO₂; —CN; —CF₃; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH;—CH₂NH₂; —CH₂SO₂CH₃; —C(O)R_(x); —CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x);—OCO₂R_(x); —OCON(R_(x))₂; —N(R_(x))₂; —S(O)₂R_(x); and—NR_(x)(CO)R_(x); wherein each occurrence of R_(x) independentlyincludes, but is not limited to, aliphatic, heteroaliphatic, aryl,heteroaryl, arylalkyl, or heteroarylalkyl, wherein any of the aliphatic,heteroaliphatic, arylalkyl, or heteroarylalkyl substituents describedabove and herein may be substituted or unsubstituted, branched orunbranched, cyclic or acyclic, and wherein any of the aryl or heteroarylsubstituents described above and herein may be substituted orunsubstituted.

The term “amphiphilic” as used herein to describe a molecule refers tothe molecule's dual hydrophobic and hydrophilic properties. Typically,amphiphilic molecules have a polar, water soluble group (e.g., aphosphate, carboxylic acid, sulfate) attached to a nonpolar,water-insoluble group (e.g., a hydrocarbon). The term amphiphilic issynonymous with amphipathic. Examples of amphiphilic molecules includesodium dodecyl (lauryl) sulfate, fatty acids, phospholipids, and bileacids. Amphiphilic molecules may be uncharged, cationic, or anionic.

As used herein, the term “dissolution rate” refers to the amount of timeit takes for an active ingredient or composition thereof (e.g., a saltmethylnaltrexone) to dissolve in a solvent. The dissolution rate maydepend on a variety of factors including mixing, temperature, pH,solvent, particle size, etc. The dissolution rate of a drug orcomposition thereof affects the bioavailability of the drug. In certaincircumstances, dissolution rate is used to determine drug availabilityfrom solid dosage forms.

As used herein, an “effective amount” of a compound or pharmaceuticallyacceptable composition or formulation can achieve a desired therapeuticand/or prophylactic effect. In some embodiments, an “effective amount”is at least a minimal amount of a compound, or formulation orcomposition containing a compound, which is sufficient for treating oneor more symptoms of a disorder or condition associated with modulationof peripheral μ opioid receptors, such as side effects associated withopioid analgesic therapy (e.g., gastrointestinal dysfunction (e.g.,dysmotility constipation, etc.), nausea, emesis, etc.). In certainembodiments, an “effective amount” of a compound, composition, orformulation containing a compound, is sufficient for treating symptomsassociated with, a disease associated with aberrant endogenousperipheral opioid or μ opioid receptor activity (e.g., idiopathicconstipation, ileus, etc.). In some embodiments, the term “effectiveamount,” as used in connection with an amount of methylnaltrexone orsalt of methylnaltrexone, means an amount of methylnaltrexone or salt ofmethylnaltrexone sufficient to achieve laxation in a patient.

The term “effervescent disintegrant,” as used herein, refers to amaterial that causes effervescence resulting in quick disintegration ofthe dosage form following contact with aqueous medium. Typically theeffervescent disintegrant is a base (e.g., carbonate) which reacts withan acid (e.g., HCl in the stomach) to form carbon dioxide. Therefore,such effervescent disintegrants include carbon dioxide producingdisintegrants. Carbonate sources include, but are not limited to,carbonate and bicarbonate salts such as sodium bicarbonate, sodiumcarbonate, potassium bicarbonate, potassium carbonate, magnesiumcarbonate, sodium sesquicarbonate, sodium glycine carbonate, L-lysinecarbonate, arginine carbonate, and calcium carbonate. Effervescentdisintegrants are known in the art for achieving fast-disintegratingdosage forms.

As used herein, the term “lipophilicity” refers to a compound's abilityto associate with or dissolve in a fat, lipid, oil, or non-polarsolvent. Lipophilicity and hydrophobicity may be used to describe thesame tendency of a molecule to dissolve in fats, oils, lipids, andnon-polar solvents.

As used herein the term “non-functional coating” is a coating that doesnot significantly affect release characteristics of a therapeuticallyactive compound or compounds from a formulation when administered.Examples of a non-functional coat include a seal coat (e.g.,hydroxypropyl cellulose, hypromellose or polyvinyl alcohol). In certainembodiments, a non-functional coating is a polish coat or seal coat.

As used herein the term “non-malignant pain” refers to “non-cancerpain.”

The term “apparent partition coefficient,” as used herein, refers to theratio of concentrations of a compound in any form in the two phases of amixture of two immiscible solvents at equilibrium. In certainembodiments, the two immiscible solvents are octanol and water. Theapparent partition coefficient may be determined under variousconditions, for example, temperature, pH, concentration, etc. Apparentpartition coefficients have been found useful in estimating thedistribution of compounds in the body. Higher apparent partitioncoefficients denote a more hydrophobic (more lipophilic) compound, whilelower apparent partition coefficients denote a hydrophilic compound. Theapparent partition coefficient of a compound may be determined byprocedures known in the art, for example, in the U.S. Pharmacopeia. Theapparent partition coefficient may be determined by the procedure usedto determine the apparent partition coefficients of methylnaltrexonedodecyl sulfate and methylnaltrexone heptyl sulfate in the Examples.

The term “subject”, as used herein, means a mammal and includes humanand animal subjects, such as domesticated animals (e.g., horses, dogs,cats, etc.) and experimental animals (e.g., mice, rats, dogs,chimpanzees, apes, etc.).

The terms “suffer” or “suffering” as used herein refers to one or moreconditions that a patient has been diagnosed with, or is suspected tohave.

The term “spheroid”, as used herein, has its art understood meaning of asubstantially spherical particulate. In many embodiments, spheroidsprepared or utilized according to the present invention have a sizewithin the range of about 1-1500 microns. In some embodiments, suchspheroids have a size within the range of about 20-1500 microns. In someembodiments, such spheroids have a size within the range of about20-1000 microns. In some embodiments, such spheroids have a size withinthe range of about 20-500 microns. In some embodiments, such spheroidshave a size within the range of about 20-300 microns. In certainembodiments, the spheroids have a size range wherein at least 80% of thespheroids fall within the range of about 20-325 microns. In someembodiments, the spheroids have a size range wherein at least 50% of thespheroids fall within the range of about 45-120 microns.

The terms “treat” or “treating,” as used herein, refers to partially orcompletely alleviating, inhibiting, delaying onset of, reducing theincidence of, ameliorating and/or relieving a disorder or condition, orone or more symptoms of the disorder, disease or condition.

“Therapeutically active agent” or “active agent” refers to a substance,including a biologically active substance, that is useful for therapy(e.g., human therapy, veterinary therapy), including prophylactic andtherapeutic treatment. Therapeutically active agents include organicmolecules that are drug compounds, peptides, proteins, carbohydrates,monosaccharides, oligosaccharides, polysaccharides, nucleoprotein,mucoprotein, lipoprotein, synthetic polypeptide or protein, smallmolecules linked to a protein, glycoprotein, steroid, nucleic acid, DNA,RNA, nucleotide, nucleoside, oligonucleotides, antisenseoligonucleotides, lipid, hormone, and vitamin. Therapeutically activeagents include any substance used as a medicine for treatment,prevention, delay, reduction or amelioration of a disease, condition, ordisorder. Among therapeutically active agents useful in the formulationsof the present invention are opioid receptor antagonist compounds,opioid analgesic compounds, and the like. Further detailed descriptionof compounds useful as therapeutically active agents is provided below.A therapeutically active agent includes a compound that increases theeffect or effectiveness of a second compound, for example, by enhancingpotency or reducing adverse effects of a second compound.

The expression “unit dosage form” as used herein refers to a physicallydiscrete unit of a provided formulation appropriate for the subject tobe treated. It will be understood, however, that the total daily usageof provided formulation will be decided by the attending physicianwithin the scope of sound medical judgment. The specific effective doselevel for any particular subject or organism will depend upon a varietyof factors including the disorder being treated and the severity of thedisorder; activity of specific active agent employed; specificformulation employed; age, body weight, general health, sex and diet ofthe subject; time of administration, and rate of excretion of thespecific active agent employed; duration of the treatment; drugs and/oradditional therapies used in combination or coincidental with specificcompound(s) employed, and like factors well known in the medical arts.

The term “pK_(a),” as used herein, refers to the −log₁₀K_(a), whereinK_(a) is the acid dissociation constant. pK_(a) measures the strength ofan acid in solution on a logarithmic scale. The acid dissociationconstant K_(a) is the equilibrium constant for the dissociation of acompound into a proton and its conjugate base, symbolically written as:HA

A⁻+H⁺.Compositions and Formulations of Methylnaltrexone

As used herein, methylnaltrexone refers to (R)—N-methylnaltrexone.(R)—N-methylnaltrexone, a peripherally acting μ opioid receptorantagonist, has been studied and used to treat bowel dysfunction inpatients being administered opioids. Surprisingly, enterically coatedpreparations of methylnaltrexone do not consistently demonstrate asubstantial effect in treating opioid-induced constipation. Contrary tothe suggestions of the prior art concerning oral methylnaltrexone, localconcentrations of methylnaltrexone in the intestinal tract remote fromthe stomach, are not effective to induce laxation and treatconstipation.

In certain embodiments, the present invention provides a compositioncomprising methylnaltrexone and a pharmaceutically acceptable excipient,wherein the composition in solution yields an octanol/water apparentpartition coefficient for methylnaltrexone of at least 0.25 under acidicconditions, in certain embodiments at a pH between 1 and 4. In someembodiments, such compositions are formulated for oral administration.In some embodiments, a composition for oral administration is formulatedinto a tablet. Methylnatrexone for use in such compositions andformulations may be in any of a variety of forms. For example, forms ofmethylnaltrexone suitable for use in the inventive compositions andformulations include pharmaceutically acceptable salts, prodrugs,polymorphs (i.e., crystal forms), co-crystals, hydrates, solvates, andthe like. Any form of methylnaltrexone may be used in the compositionsor formulations, but the form should allow for ion pairing with theamphiphilic pharmaceutically acceptable excipient.

In certain embodiments, the compositions, and formulations thereof,comprise a salt of formula I:

wherein A⁻ is a suitable anion. In certain embodiments, A⁻ is the anionof a Brønsted acid. Exemplary Brønsted acids include hydrogen halides,carboxylic acids, sulfonic acids, sulfuric acid, and phosphoric acid. Incertain embodiments, A⁻ is chloride, bromide, iodide, fluoride, sulfate,bisulfate, tartrate, nitrate, citrate, bitartrate, carbonate, phosphate,malate, maleate, fumarate sulfonate, methylsulfonate, formate,carboxylate, sulfate, methylsulfate or succinate salt. In certainembodiments, A⁻ is trifluoroacetate. In certain embodiments, A⁻ isbromide. In certain embodiments, A⁻ is an anion of an amphiphilicpharmaceutically acceptable excipient. In certain embodiments, A⁻ is anacidic amphiphilic pharmaceutically acceptable excipient. In certainembodiments, the pharmaceutically acceptable excipient has a pK_(a) ofabout 3 or less. In certain embodiments, the pharmaceutically acceptableexcipient has a pK_(a) of about 2 or less. In certain embodiments, thepharmaceutically acceptable excipient has a pK_(a) between about 1 andabout 2. In certain embodiments, the pharmaceutically acceptableexcipient has a pK_(a) of about 1 or less. In certain embodiments, theanion of the pharmaceutically acceptable excipient include a sulfate,sulfonate, phosphate, phosphonate, nitrate, or nitrite moiety. Incertain embodiments, the anion of the pharmaceutically acceptableexcipient includes a sulfate (—OSO₃ ⁻) group. In certain embodiments,the anion is butyl sulfate, pentyl sulfate, hexyl sulfate, heptylsulfate, octyl sulfate, nonyl sulfate, decyl sulfate, undecyl sulfate,dodecyl sulfate, tridecyl sulphate, tetradecyl sulfate, pentadecylsulfate, hexadecyl sulfate, heptadecyl sulfate, octadecyl sulfate,eicosyl sulfate, docosyl sulfate, tetracosyl sulfate, hexacosyl sulfate,octacosyl sulfate, and triacontyl sulphate. In certain embodiments, themethylnaltrexone in the composition or formulation may have multipleanions (e.g., bromide and dodecyl (lauryl) sulfate) associate with it.

In some embodiments, the compositions, and formulations thereof,comprise (R)—N-methylnaltrexone bromide. (R)—N-methylnaltrexone bromide,which is also known as “MNTX” and is described in international PCTpatent application publication number, WO2006/12789, which isincorporated herein by reference. The chemical name for(R)—N-methylnaltrexone bromide is(R)—N-(cyclopropylmethyl)noroxymorphone methobromide.(R)—N-methylnaltrexone bromide has the molecular formula C₂₁H₂₆NO₄Br anda molecular weight of 436.36 g/mol. (R)—N-methylnaltrexone bromide hasthe following structure:

(R)—N-methylnaltrexone bromide

where the compound is in the (R) configuration with respect to thequaternary nitrogen. In certain embodiments of the present invention, atleast about 99.6%, 99.7%, 99.8%, 99.85%, 99.9%, or 99.95% of thecompound is in the (R) configuration with respect to nitrogen. Methodsfor determining the amount of (R)—N-methylnaltrexone bromide, present ina sample as compared to the amount of (S)—N-methylnaltrexone bromidepresent in that same sample, are described in detail in WO2006/127899,which is incorporated herein by reference. In other embodiments, themethylnaltrexone contains 0.15%, 0.10%, or less (S)—N-methylnaltrexonebromide.

In some embodiments, a composition, or formulation thereof, comprisesfrom about 7% to about 75%, about 25% to about 55%, about 40%, or toabout 50% (R)—N-methylnaltrexone cation, based upon total weight of theformulation. In certain embodiments, a provided composition, orformulation thereof, comprises from about 7%, about 8%, about 10%, about20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 75%(R)—N-methylnaltrexone cation, based upon the total weight of the givencomposition or formulation. It will be understood that the(R)—N-methylnaltrexone cation and the anion of the amphiphilicpharmaceutically acceptable excipient may exist in the composition as anion pair or may exist as separate salts paired with other counter ionssuch as bromide and sodium, or mixtures thereof.

In some embodiments, a composition, or formulation thereof, comprisesfrom about 7% to about 75%, about 25% to about 55%, about 40%, or toabout 50% (R)—N-methylnaltrexone cation and dodecyl sulfate anion, basedupon the total weight of the composition or formulation. In certainembodiments, a composition, or formulation thereof, comprises from about7%, about 8%, about 10%, about 20%, about 30%, about 40%, about 50%,about 60%, about 70%, or about 75% (R)—N-methylnaltrexone cation anddodecyl sulfate anion, based upon total weight of the composition orformulation.

In certain embodiments, the present invention provides a compositioncomprising methylnaltrexone and an amphiphilic pharmaceuticallyacceptable excipient. The amphiphlic pharmaceutically acceptableexcipient increases the lipophilicity of the composition therebyallowing for increased transport through the unstirred diffusion layerin the GI tract, resulting in increased permeation through biologicalmembranes. In certain embodiments, the excipient increases thelipophilicity of the drug. In certain embodiments, the excipient is asurfactant. In some embodiments, the excipient is an anionic surfactant.In certain embodiments, the excipient is an anionic surfactant thatforms an ion pair or salt with positively charged methylnaltrexone. Suchanionic surfactants are known in the art and are typically characterizedby having a lipophilic end and an anionic portion. Exemplary excipientsuseful in the present invention include aliphatic sulfates (e.g., sodiumdodecyl (lauryl) sulfate), aliphatic phosphates, fatty acids, and saltsand derivatives thereof.

As a measure of lipophilicity of the resulting ion pair, a solution ofthe composition yields an apparent octanol/water partition coefficientfor methylnaltrexone of at least 0.25 at a pH between 1 and 4. Theapparent octanol/water partition coefficient as used herein isdetermined at room temperature at a concentration of approximately 0.5mg/mL. Exemplary methods for the determination of apparent octanol/waterpartition coefficient of methylnaltrexone salts are described in theExamples below.

Particularly useful amphiphilic pharmaceutically acceptable excipientincludes those that increase the oral absorption of methylnaltrexone. Incertain embodiments, the excipient increases the absorption ofmethylnaltrexone in the stomach. In certain embodiments, the excipientincreases the ability of methylnaltrexone to cross lipophilic barriers.In certain embodiments, the excipient increases the lipophilicity ofmethylnaltrexone by forming an ion pair with cationic methylnaltrexone.Ion pairing increases the partitioning of methylnaltrexone into anorganic phase such as a lipid bilayer. In certain embodiments, theexcipient forms an ion pair with methylnaltrexone such that when thecomposition is in solution, the methylnaltrexone has an apparentoctanol/water partition coefficient of at least 0.25 at a pH between 1and 4. In certain embodiments, the apparent octanol/water partitioncoefficient is at least 0.5 at a pH between 1 and 4. In certainembodiments, the apparent octanol/water partition coefficient is atleast 0.75 at a pH between 1 and 4. In certain embodiments, the apparentoctanol/water partition coefficient is at least 1.0 at a pH between 1and 4. In certain embodiments, the apparent octanol/water partitioncoefficient is at least 10 at a pH between 1 and 4. In certainembodiments, the apparent octanol/water partition coefficient is atleast 15 at a pH between 1 and 4. In certain embodiments, the apparentoctanol/water partition coefficient is at least 20 at a pH between 1 and4. In certain embodiments, the apparent octanol/water partitioncoefficient is at least 25 at a pH between 1 and 4. In certainembodiments, the apparent octanol/water partition coefficient is atleast 30 at a pH between 1 and 4.

As used herein, the term “aliphatic sulfate” refers to a compound havinga sulfate moiety at one end and an aliphatic tail, which is straight orbranched, and saturated or unsaturated. The aliphatic tail may besubstituted and may also include cyclic groups. In some embodiments, thealiphatic tail is a C₄ to C₃₀ aliphatic group. In certain embodiments,the aliphatic tail is a C₇ to C₂₀ aliphatic group. In certainembodiments, the aliphatic tail is a C₁₀ to C₂₀ aliphatic group. Incertain embodiments, the aliphatic tail is a C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, orC₁₅ aliphatic group. In certain embodiments, the aliphatic group is ann-alkyl group, which is saturated, not branched, and not substituted. Incertain embodiments, the aliphatic group is C₇-C₂₀ n-alkyl. In certainembodiments, the aliphatic group is C₁₀-C₁₅ n-alkyl.

In certain embodiments, the amphiphilic pharmaceutically acceptableexcipient is a compound of formula:R¹—OSO₂OHor a salt thereof, wherein R¹ is a C₄₋₃₀ aliphatic group that issaturated or unsaturated, unbranched or branched, and cyclic or acyclic,and the aliphatic group is optionally substituted with one or morehalogen or hydroxyl groups. In certain embodiments, each R¹ is a C₄₋₁₀aliphatic group. In certain embodiments, each R¹ is a C₁₀₋₁₅ aliphaticgroup. In certain embodiments, each R¹ is a C₁₅₋₂₀ aliphatic group. Incertain embodiments, each R¹ is a C₂₀₋₃₀ aliphatic group. In certainembodiments, R¹ is unsaturated. In certain embodiments, R¹ is saturated.In certain embodiments, R¹ is unbranched. In certain embodiments, R¹ isbranched. In certain embodiments, R1 is substituted. In certainembodiments, R¹ is unsubstituted. In certain embodiments, R¹ issaturated, unbranched, and unsubstituted. In certain embodiments, R¹ isC₄₋₃₀ n-alkyl. In certain embodiments, R¹ is C₅₋₁₅ n-alkyl. In certainembodiments, R¹ is C₅₋₁₀ n-alkyl. In certain embodiments, R¹ is C₁₀₋₁₅n-alkyl. In certain embodiments, R¹ is C₆ n-alkyl. In certainembodiments, R¹ is C₇ n-alkyl. In certain embodiments, R¹ is C₈ n-alkyl.In certain embodiments, R¹ is C₉ n-alkyl. In certain embodiments, R¹ isC₁₀ n-alkyl. In certain embodiments, R¹ is C₁₁ n-alkyl. In certainembodiments, R¹ is C₁₂ n-alkyl. In certain embodiments, R¹ is C₁₃n-alkyl. In certain embodiments, R¹ is C₁₄ n-alkyl. In certainembodiments, R¹ is C₁₅ n-alkyl. In certain embodiments, the excipient isa sodium salt form.

In certain embodiments, the amphiphilic pharmaceutically acceptableexcipient is a compound of formula:R¹—SO₂OHor a salt thereof, wherein R¹ is a C₄₋₃₀ aliphatic group that issaturated or unsaturated, unbranched or branched, and cyclic or acyclic,and the aliphatic group is optionally substituted with one or morehalogen or hydroxyl groups. In certain embodiments, each R¹ is a C₄₋₁₀aliphatic group. In certain embodiments, each R¹ is a C₁₀₋₁₅ aliphaticgroup. In certain embodiments, each R¹ is a C₁₅₋₂₀ aliphatic group. Incertain embodiments, each R¹ is a C₂₀₋₃₀ aliphatic group. In certainembodiments, R¹ is unsaturated. In certain embodiments, R¹ is saturated.In certain embodiments, R¹ is unbranched. In certain embodiments, R¹ isbranched. In certain embodiments, R1 is substituted. In certainembodiments, R¹ is unsubstituted. In certain embodiments, R¹ issaturated, unbranched, and unsubstituted. In certain embodiments, R¹ isC₄₋₃₀ n-alkyl. In certain embodiments, R¹ is C₅₋₁₅ n-alkyl. In certainembodiments, R¹ is C₅₋₁₀ n-alkyl. In certain embodiments, R¹ is C₁₀₋₁₅n-alkyl. In certain embodiments, R¹ is C₆ n-alkyl. In certainembodiments, R¹ is C₇ n-alkyl. In certain embodiments, R¹ is C₈ n-alkyl.In certain embodiments, R¹ is C₉ n-alkyl. In certain embodiments, R¹ isC₁₀ n-alkyl. In certain embodiments, R¹ is C₁₁ n-alkyl. In certainembodiments, R¹ is C₁₂ n-alkyl. In certain embodiments, R¹ is C₁₃n-alkyl. In certain embodiments, R¹ is C₁₄ n-alkyl. In certainembodiments, R¹ is C₁₅ n-alkyl. In certain embodiments, the excipient isa sodium salt form.

In certain embodiments, the amphiphilic pharmaceutically acceptableexcipient is a compound of formula:R¹—P(O)₂OHor a salt thereof, wherein R¹ is a C₄₋₃₀ aliphatic group that issaturated or unsaturated, unbranched or branched, and cyclic or acyclic,and the aliphatic group is optionally substituted with one or morehalogen or hydroxyl groups. In certain embodiments, each R¹ is a C₄₋₁₀aliphatic group. In certain embodiments, each R¹ is a C₁₀₋₁₅ aliphaticgroup. In certain embodiments, each R¹ is a C₁₅₋₂₀ aliphatic group. Incertain embodiments, each R¹ is a C₂₀₋₃₀ aliphatic group. In certainembodiments, R¹ is unsaturated. In certain embodiments, R¹ is saturated.In certain embodiments, R¹ is unbranched. In certain embodiments, R¹ isbranched. In certain embodiments, R1 is substituted. In certainembodiments, R¹ is unsubstituted. In certain embodiments, R¹ issaturated, unbranched, and unsubstituted. In certain embodiments, R¹ isC₄₋₃₀ n-alkyl. In certain embodiments, R¹ is C₅₋₁₅ n-alkyl. In certainembodiments, R¹ is C₅₋₁₀ n-alkyl. In certain embodiments, R¹ is C₁₀₋₁₅n-alkyl. In certain embodiments, R¹ is C₆ n-alkyl. In certainembodiments, R¹ is C₇ n-alkyl. In certain embodiments, R¹ is C₈ n-alkyl.In certain embodiments, R¹ is C₉ n-alkyl. In certain embodiments, R¹ isC₁₀ n-alkyl. In certain embodiments, R¹ is C₁₁ n-alkyl. In certainembodiments, R¹ is C₁₂ n-alkyl. In certain embodiments, R¹ is C₁₃n-alkyl. In certain embodiments, R¹ is C₁₄ n-alkyl. In certainembodiments, R¹ is C₁₅ n-alkyl. In certain embodiments, the excipient isa sodium salt form.

In certain embodiments, the amphiphilic pharmaceutically acceptableexcipient is a compound of formula:R¹—OP(O)₂OHor a salt thereof, wherein R¹ is a C₄₋₃₀ aliphatic group that issaturated or unsaturated, unbranched or branched, and cyclic or acyclic,and the aliphatic group is optionally substituted with one or morehalogen or hydroxyl groups. In certain embodiments, each R¹ is a C₄₋₁₀aliphatic group. In certain embodiments, each R¹ is a C₁₀₋₁₅ aliphaticgroup. In certain embodiments, each R¹ is a C₁₅₋₂₀ aliphatic group. Incertain embodiments, each R¹ is a C₂₀₋₃₀ aliphatic group. In certainembodiments, R¹ is unsaturated. In certain embodiments, R¹ is saturated.In certain embodiments, R¹ is unbranched. In certain embodiments, R¹ isbranched. In certain embodiments, R1 is substituted. In certainembodiments, R¹ is unsubstituted. In certain embodiments, R¹ issaturated, unbranched, and unsubstituted. In certain embodiments, R¹ isC₄₋₃₀ n-alkyl. In certain embodiments, R¹ is C₅₋₁₅ n-alkyl. In certainembodiments, R¹ is C₅₋₁₀ n-alkyl. In certain embodiments, R¹ is C₁₀₋₁₅n-alkyl. In certain embodiments, R¹ is C₆ n-alkyl. In certainembodiments, R¹ is C₇ n-alkyl. In certain embodiments, R¹ is C₈ n-alkyl.In certain embodiments, R¹ is C₉ n-alkyl. In certain embodiments, R¹ isC₁₀ n-alkyl. In certain embodiments, R¹ is C₁₁ n-alkyl. In certainembodiments, R¹ is C₁₂ n-alkyl. In certain embodiments, R¹ is C₁₃n-alkyl. In certain embodiments, R¹ is C₁₄ n-alkyl. In certainembodiments, R¹ is C₁₅ n-alkyl. In certain embodiments, the excipient isa sodium salt form.

One of ordinary skill in the art will recognize that methylnaltrexonemay form an ion pair or salt with an anionic amphiphilicpharmaceutically acceptable excipient. In some embodiments, the presentinvention provides a compound of formula II:

wherein A⁻ is an anionic amphiphilic pharmaceutically acceptableexcipient.

In some aspects, methylnaltrexone may form an ion pair with any offormulae R¹—COOH, R¹—SO₂OH, R¹—OSO₂OH, R¹—P(O)₂OH, R¹—OP(O)₂OH, or asalt thereof, as described herein. Thus, according to anotherembodiment, the present invention provides a compound of any of formulaIII, formula IV, formula V, formula VI, or formula VII:

wherein R¹ is a C₄₋₃₀ aliphatic group that is saturated or unsaturated,unbranched or branched, and cyclic or acyclic, and the aliphatic groupis optionally substituted with one or more halogen or hydroxyl groups.

In some embodiments, the amphiphilic pharmaceutically acceptableexcipient is sodium dodecyl (lauryl) sulfate (also known as SDS or SLS),sodium heptyl sulfate, sodium heptyl sulfonate, perfluorooctanesulfonate(PFOS), and the like.

In some embodiments, compositions, i.e., pharmaceutical compositionscomprising methylnaltrexone and sodium dodecyl (lauryl) sulfate (alsoknown as SDS or SLS), are provided.

In some embodiments, a provided composition, or formulation thereof,comprises from about 5% to about 80% of the amphiphilic pharmaceuticallyacceptable excipient, based upon total weight of the composition, orformulation thereof. In certain embodiments, about 5% to about 25% ofamphiphilic pharmaceutically acceptable excipient is used in thecomposition or formulation. In some embodiments, a provided composition,or formulation thereof, comprises about 5%, about 10%, about 15%, about20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,about 55%, about 60%, about 65%, about 70%, about 75%, or about 80% ofthe excipient, based upon total weight of the composition, orformulation thereof.

Certain amphiphilic pharmaceutically acceptable excipients and theircorresponding methylnaltrexone ion pairs are less soluble compared tomethylnaltrexone bromide in an aqueous environment. In certainembodiments, therefore, the present invention provides a composition orformulation comprising methylnaltrexone, or a salt thereof, anamphiphilic pharmaceutically acceptable excipient, and a disintegrant.Incorporation of a suitable rapid-acting disintegrant into compositionsand formulations facilitates the breakdown of tablets or other soliddosage forms, in particular, the rapid breakdown of tablets or othersolid dosage forms in the stomach. Thus, the inclusion of rapid-actingdisintegrants is desired in solid dosage forms, such as tablets, thatcontain active ingredient. The amount of the disintegrant will vary,depending on the nature and amount of the amphiphilic pharmaceuticallyacceptable excipient (and, optionally, other ingredients). Those skilledin the art will understand how to manufacture a solid dosage form whichwill dissolve in the stomach according to the parameters describedabove. There exist in vitro models, for making such determinations, suchas the United States Pharmacopeia (USP) dissolution test, the USPdisintegration test, etc. In some embodiments, at least 50% of themethylnaltrexone in the composition dissolves in 15 minutes. In otherembodiments, at least 75%, 80%, 85%, 90%, 95%, or even 99% of themethylnaltrexone in the composition dissolves in 15 minutes. In someembodiments, the amounts of methylnaltrexone indicated above dissolve inabout 10 minutes, or even about 5 minutes. As used herein by dissolve acertain percent in the stomach within a particular time period, it ismeant the percent of the methylnaltrexone, as a cation or as a salt suchas an ion pair, in the composition that will convert from a solid intosolution when the composition is placed in 900 ml of 1 N HCl at 37° C.,100 rpm Paddle.

Suitable disintegrants are known in the art and include, but are notlimited to, agar, calcium carbonate, potato or tapioca starch, alginicacid, certain silicates, sodium carbonate, sodium bicarbonate,crospovidone (cross-linked PVP), sodium carboxymethyl starch (sodiumstarch glycolate), cross-linked sodium carboxymethyl cellulose(croscarmellose), pregelatinized starch (starch 1500), microcrystallinestarch, water insoluble starch, calcium carboxymethyl cellulose,magnesium aluminum silicate (Veegum), and combinations thereof. In someembodiments, the disintegrant is crospovidone. In certain embodiments,the disintegrant is an effervescent disintegrant. Effervescentdisintegrants are capable of generating carbon dioxide in an aqueousmedium, particularly acidic aqueous medium such as the contents of thestomach. In certain embodiments, the disintegrant is a bicarbonate, suchas sodium bicarbonate (NaHCO₃) or potassium bicarbonate (KHCO₃). Incertain embodiments, the disintegrants is a carbonate. In certainembodiments, the disintegrant is sodium carbonate (Na₂CO₃). In certainembodiments, the disintegrant is calcium carbonate (CaCO₃). In certainembodiments, the composition or formulation comprises at least twodisintegrants. For example, the composition or formulation may includeone effervescent disintegrant and one disintegrant that is noteffervescent. In certain embodiments, the compositions or formulationcomprises sodium bicarbonate and crospovidone as disintegrants. In someembodiments, provided formulations comprise from about 1% to about 25%,about 1% to about 15%, about 1% to about 10%, or about 2% to about 5%disintegrant, based upon total weight of the formulation. In someembodiments, provided formulations comprise from about 1%, about 2%,about 3%, about 4%, about 5%, about 7%, about 8%, about 10%, about 12%,or about 15% disintegrant, based upon total weight of the formulation.In certain embodiments, the composition or formulation includes amaterial and/or coating that retards or prevents dissolution of thesolid dosage form in the oral cavity. Preferably, the solid dosage formbreaks down or disintegrates rapidly in the stomach, not in the oralcavity.

In some embodiments, the present invention provides a formulation ofmethylnatrexone which further comprises one or more additionalcomponents, such as, for example, binders, carriers, disintegrants,chelating agents, antioxidants, fillers, wetting agents, or combinationsthereof. In certain embodiments, a composition is formulated into atablet which further comprises one or more additional components, suchas, for example, binders, carriers, disintegrants, chelating agents,antioxidants, fillers, wetting agents, lubricants, or combinationsthereof. In some embodiments, a composition is formulated into a tabletwhich further comprises an antioxidant and one or more components, suchas, for example, binders, carriers, chelating agents, fillers, wettingagents, or combinations thereof. In some embodiments, a composition isformulated into a tablet which further comprises a disintegrant and oneor more components, such as, for example, binders, carriers, chelatingagents, antioxidants, fillers, wetting agents, or combinations thereof.In some embodiments, a composition is formulated into a tablet whichfurther comprises an antioxidant, a disintegrant, and one or morecomponents, such as, for example, binders, carriers, chelating agents,fillers, wetting agents, or combinations thereof. Such additionalcomponents are described in detail herein, infra.

In certain embodiments, pharmaceutically acceptable formulations of thepresent invention are provided as tablets which comprise a compositioncomprising methylnaltrexone and an amphiphilic pharmaceuticallyacceptable excipient, and a disintegrant, and, optionally, one or moreof a binder, a chelating agent, and a wetting agent. In some embodimentssuch tablets comprise a composition comprising methylnaltrexone and anamphiphilic pharmaceutically acceptable excipient, a binder, a chelatingagent, a disintegrant, and a wetting agent. In certain embodiments suchtablets comprise a composition comprising methylnaltrexone and anamphiphilic pharmaceutically acceptable excipient, an antioxidant, andone or more of a binder, a chelating agent, a disintegrant, and awetting agent. According to some embodiments, provided formulationscomprise tablets that have a non-functional coating. In someembodiments, provided formulations further comprise an antioxidant.

One skilled in the art will readily appreciate that the category underwhich a particular component is listed is not intended to be limiting;in some cases a particular component might appropriately fit into morethan one category. Also, as will be appreciated, the same component cansometimes perform different functions, or can perform more than onefunction, in the context of a particular formulation, for exampledepending upon the amount of the ingredient and/or the presence of otheringredients and/or active compound(s).

Wetting agents are well known in the art and typically facilitate theinteraction of an active agent, such as one that is hydrophobic, withwater molecules in a surrounding aqueous environment. Exemplary wettingagents include poloxamer, polyoxyethylene ethers, polyoxyethylenesorbitan fatty acid esters polyoxyethylene fatty acid esters,polyethylene glycol fatty acid esters, polyoxyethylene hydrogenatedcastor oil, polyoxyethylene alkyl ether, polysorbates, such aspolysorbate 80, cetyl alcohol, glycerol fatty acid esters (e.g.,triacetin, glycerol monostearate, and the like), polyoxymethylenestearate, sodium dodecyl sulfate, sorbitan fatty acid esters, sucrosefatty acid esters, benzalkonium chloride, polyethoxylated castor oil,and docusate sodium, and the like, and combinations thereof. In someembodiments, provided tablets comprise from about 1% to about 25%wetting agent, based upon total weight of the tablets. In someembodiments, provided tablets comprise from about 1%, about 3%, about4%, about 5%, about 10%, about 15%, or about 20% of wetting agent, basedupon total weight of given tablets.

In certain embodiments, a wetting agent is a polysorbate. In someembodiments, a wetting agent is polysorbate 80, also known as Tween 80,and is available from Sigma-Aldrich, among other sources. In someembodiments, provided tablets comprise from about 1% to about 25%polysorbate 80, about 1% to about 5%, about 2% to about 5%, about 3%, orto about 4% based upon total weight of given tablet. In certainembodiments, provided tablets comprise from about 1%, about 3%, about4%, about 5%, about 10%, about 15%, or about 20% polysorbate 80, basedupon total weight of given tablets. Without wishing to be bound by anyparticular theory, polysorbate 80 can also act as an absorptionenhancer. Further, without wishing to be bound by any particular theory,polysorbate 80 may facilitate thinning of the mucus layer created in thegastrointestinal tract so that remaining methylnaltrexone in the mucouslayer is more readily released for rapid absorption.

Addition of one or more chelating agents may be particularly useful informulations that include methylnaltrexone, and such agents may provideprotection from metal-catalyzed degradation and/or from precipitation ofmethylnaltrexone. Appropriate chelating agents are known to thoseskilled in the art, and include any pharmaceutically acceptablechelating agent. Common chelating agents include, but are not limited toethylenediaminetetraacetic acid (EDTA) and derivatives thereof, ethyleneglycol-bis-(2-aminoethyl)-N,N,N′,N′-tetraaceticacid (EGTA) andderivatives thereof, diethylenetriaminepentaacetic acid (DTPA) andderivatives thereof, N,N-bis(carboxymethyl)glycine (NTA) and derivativesthereof, nitrilotriacetic acid and derivatives thereof, citric acid andderivatives thereof, niacinamide and derivatives thereof, and sodiumdesoxycholate and derivatives thereof.

In some embodiments, the chelating agent is selected from the groupconsisting of EDTA or derivatives thereof. In some embodiments, thechelating agent is selected from the group consisting of calcium EDTAdisodium, diammonium EDTA, dipotassium EDTA, disodium EDTA, TEA-EDTA,tetrasodium EDTA, tripotassium EDTA, trisodium EDTA, HEDTA, andtrisodium HEDTA, and related salts thereof. In some embodiments, thechelating agent is EDTA disodium, EDTA trisodium, or calcium EDTAdisodium. In some embodiments, the chelating agent is calcium EDTA(edetate calcium) or a calcium salt EDTA derivative or calcium EGTA or acalcium salt EGTA derivative. In some embodiments, the chelating agentis calcium EDTA disodium, such as, for example, calcium EDTA disodiumhydrate (edetate calcium disodium dihydrate). Calcium EDTA is availablefrom Sigma-Aldrich, among other sources. In some embodiments, providedformulations comprise from about 0.01% to about 5%, about 0.01% to about4%, about 0.01% to about 3%, 0.01% to about 2%, 0.01% to about 1%, about0.1% to about 5%, about 0.1% to about 4%, 0.1% to about 4%, about 0.1%to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, or about0.1% to about 0.5% of the chelating agent, based upon total weight ofthe formulation. In some embodiments, provided formulations comprisefrom about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, orabout 0.6% of the chelating agent, based upon total weight offormulation.

Suitable binders (also referred to as “diluents” and/or “fillers”) areknown in the art. For example, suitable binders include but are notlimited to starch, PVP (polyvinyl pyrrolidone), low molecular weight HPC(hydroxypropyl cellulose), microcrystalline cellulose (e.g., Avicel®),silicified microcrystalline cellulose (Prosolv 50), low molecular weightHPMC (hydroxypropyl methylcellulose), low molecular weight carboxymethylcellulose, ethylcellulose, alginates, gelatin, polyethylene oxide,acacia, dextrin, sucrose, magnesium aluminum silicate, andpolymethacrylates. Fillers include agents selected from the groupconsisting of microcrystalline cellulose (e.g., Avicel®), starch,lactitol, lactose, a suitable inorganic calcium salt, sucrose, glucose,mannitol, silicic acid, or a combination thereof. In some embodiments,formulations comprise from about 5%, to about 90%, or about 10% to about50%, or about 10% to about 40%, or about 10% to about 45% binder, basedupon total weight of the formulation. In some embodiments, formulationscomprise from about 10%, about 15%, about 16%, about 20%, about 24%,about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%binder, based upon total weight of the tablets. In some embodiments,formulations comprise microcrystalline cellulose as a binder. In certainembodiments, formulations comprise the binders, microcrystallinecellulose and silicified microcrystalline cellulose.

In certain embodiments, provided formulations may comprise one or moreantioxidants. Such antioxidants include those known to one of ordinaryskill in the art. Exemplary antioxidants include ascorbic acid, andsalts and esters thereof; citric acid, and salts and esters thereof;butylated hydroxyanisole (“BHA”); butylated hydroxytoluene (“BHT”);tocopherols (e.g., d-alpha tocopherol, dl-alpha tocopherol, d-alphatocopherol acetate, dl-alpha tocopherol acetate, beta tocopherol, deltatocopherol, gamma tocopherol, and the like), and carotenoids (e.g.,vitamin A, lutein, and zeaxanthin). In certain embodiments, aformulation comprises ascorbic acid. In some embodiments, a formulationcomprises up to about 10% one or more antioxidants by weight. In someembodiments, a provided formulation comprises about 0.01% to about 5%one or more antioxidants by weight. In some embodiments, a providedformulation comprises about 1.0% to about 10% one or more antioxidantsby weight. In certain embodiments, a provided formulation comprisesabout 1%, about 2%, about 5%, about 6%, about 7%, about 8%, about 9%, orabout 10% of one or more antioxidants by weight.

In certain embodiments, formulations may comprise a lubricant.Lubricants, generally, are substances used in solid dosage formulationsto reduce friction during compression. Such compounds include, by way ofexample and without limitation, sodium oleate, sodium stearate, calciumstearate, zinc stearate, magnesium stearate, polyethylene glycol, talc,mineral oil, stearic acid, sodium benzoate, sodium acetate, sodiumchloride, and other materials known to one of ordinary skill in the art.In certain embodiments, the lubricant is a stearate salt. In someembodiments, formulations comprise from about 0.1% to about 7%, or about0.2% to about 1% lubricant, based upon total weight of givenformulation. In certain embodiments, the lubricant is magnesium stearateand is available from Sigma-Aldrich, among other sources.

In certain embodiments, formulations may comprise a non-functionalcoating. For example, in some embodiments, the tablet may comprise anon-functional coating. In some embodiments, the non-functional coatingis a seal coat. For example, a suitable seal coating can be applied as asolution (e.g., HPMC solution) at a concentration of about 1% w/w to 25%w/w, and preferably 1% w/w to about 10% w/w. Upon drying, under suitableconditions, initial seal coating is in the range of about 1% w/w toabout 3% w/w, or about 2% w/w, of the uncoated tablet. Such a sealcoating may comprise a polymer (e.g., HPMC) and may be a commerciallyavailable seal coating seal such as Opadry® Clear (Colorcon, Inc.), orHPMC E3. Upon drying, seal coating may be from about 1% to about 10% ofweight gain of the total coated formulation. In certain embodiments, theformulation may comprise a coating to prevent disintegration of thedosage form in the oral cavity.

In certain embodiments, the formulation for oral administrationcomprises (a) about 7% to about 75% of methylnaltrexone bromide, basedupon the total weight of the formulation; (b) about 5% to about 80% ofan amphiphilic pharmaceutically acceptable excipient, based upon thetotal weight of the formulation; (c) about 0.01% to about 5% of achelating agent, based upon the total weight of the formulation; (d)about 1% to about 25% of a wetting agent, based upon the total weight ofthe formulation; (e) about 5% to about 90% of a binder, based upon thetotal weight of the formulation; (f) about 1% to about 25% of adisintegrant, based upon the total weight of the formulation; (g) about0.1% to about 7% of a lubricant, based upon the total weight of theformulation; and optionally, (h) about 0.01% to about 5% of anantioxidant, based upon the total weight of the formulation. In certainembodiments, the methylnaltrexone bromide of the formulation is(R)—N-methylnaltrexone bromide. In certain embodiments, the amphiphilicpharmaceutically acceptable excipient is sodium dodecyl (lauryl)sulfate. In certain embodiments, the chelating agent is a salt of EDTA(e.g., calcium EDTA). In certain embodiments, the wetting agent ispolysorbate 80. In certain embodiments, the disintegrant is sodiumbicarbonate. In other embodiments, the disintegrant is crospovidone. Incertain embodiments, the disintegrant is a combination of sodiumbicarbonate and crospovidone. In certain embodiments, the lubricant ismagnesium stearate. In certain embodiments, the antioxidant is ascorbicacid. In certain embodiments, the invention provides a tabletformulation for oral administration comprising about 30%methylnaltrexone bromide, about 10% sodium dodecyl sulfate, about 11%microcrystalline cellulose, about 5% crospovidone, about 0.25% calciumEDTA, about 2% polysorbate 80, about 30% Prosolv 50, about 11% sodiumbicarbonate, about 2% talc, about 0.5% silicon dioxide colloidal, andabout 0.25 magnesium stearate. It will be understood by those skilled inthe art that, depending on the manner of making the tablet or otherformulation of the invention described herein, the methylnaltrexone mayexist paired with bromide, paired with the anion of the amphiphilicpharmaceutically acceptable excipient, or some combination thereof.

Production

In certain embodiments, compositions and formulations are prepared bymethods which include an extrusion/spheronization step. In someembodiments, formulations are manufactured via wet-granulation of aprovided formulation followed by extrusion/spheronization to formspheroids. Given spheroids are then dried and milled to form a powderwhich is blended with suitable binder(s) and disintegrant(s). Theresulting mixture is then milled and blended with a suitable lubricantand pressed into tablets. In certain embodiments, a non-functionalcoating is applied.

In some embodiments, tablets are prepared by methods which do notinclude extrusion/spheronization steps and, in accordance with suchmethods, are manufactured via wet-granulation. Once dried, thegranulation is milled to form a granular powder which is blended withsuitable binder(s) and disintegrant(s). The resulting mixture is thenmilled and blended with a suitable lubricant and pressed into tablets.In certain embodiments, a non-functional coating is applied.

Unit Dosage Form

Formulations of methylnatrexone may be prepared as a unit dosage form.Indeed, a tablet is typically a unit dosage form. In some embodiments, aunit dosage form contains 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg,175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg,400 mg, 425 mg, 450 mg, 475 mg, or 500 mg, 525 mg, 550 mg, 575 mg, 600mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg,1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg, 1175 mg, 1200 mg, 1225 mg,1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg,1450 mg, 1475 mg, or 1500 mg of methylnaltrexone bromide. In someembodiments, a unit dosage form contains between 50 mg and 900 mg,inclusive, or between 150 mg and 450 mg, inclusive, of methylnaltrexonebromide. In some embodiments, a unit dosage form contains 50 mg, 75 mg,150 mg, 225 mg, 300 mg, 450 mg, 600 mg, or 900 mg of methylnaltrexonebromide. In some embodiments, the unit dosage form comprisesmethylnaxtrexone and an amphiphilic pharmaceutically acceptableexcipient, e.g., sodium dodecyl (lauryl) sulfate (also known as SDS orSLS).

Administration

Compositions and formulations may be administered to a patient asrequired to provide an effective amount of methylnaltrexone. In certainembodiments, the patient is orally administered methylnaltrexone or aformulation thereof at least once a day. In other embodiments, thepatient is orally administered methylnaltrexone or a formulation thereofup to once a day. In certain embodiments, the patient is orallyadministered methylnaltrexone or a formulation thereof not more thanonce a day. In certain embodiments, the patient is orally administeredmethylnaltrexone or a formulation thereof as needed. In certainembodiments, the patient is orally administered methylnaltrexone or aformulation thereof as needed, but not more than once a day. Forexample, a unit dosage form of a provided formulation may be orallyadministered to a patient in a single day, for example, a unit dosage ofabout 150 mg, 300 mg, or 450 mg methylnaltrexone bromide or anequivalent molar amount of methylnaltrexone. In some embodiments, thepresent invention provides a method for treating an opioid-induced sideeffect in a patient in need thereof, comprising the step of orallyadministering to said patient one or more tablets of the presentinvention wherein said tablet provides about 150 mg, 300 mg, or 450 mgof methylnaltrexone or an equivalent molar amount of methylnaltrexonebromide, e.g., methylnaltrexone and a amphiphilic pharmaceuticallyacceptable excipient such as sodium dodecyl (lauryl) sulfate (also knownas SDS or SLS), sodium heptyl sulfate, sodium heptyl sulfonate,perfluorooctanesulfonate (PFOS), and the like. In certain embodiments, asingle tablet formulation of the present invention provides about 25 mg,about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg,about 300 mg, or about 450 mg of methylnaltrexone bromide, or equivalentmoles of another salt form, or methylnaltrexone and an amphiphilicpharmaceutically acceptable excipient such as sodium dodecyl (lauryl)sulfate (also known as SDS or SLS).

As defined above, in certain embodiments the term “effective amount,” asused in connection with an amount of methylnaltrexone, means an amountof methylnaltrexone sufficient to achieve laxation in a patient. In someembodiments, an effective amount means an amount of methylnaltrexonesufficient to achieve laxation in a patient within about 24 hours,within about 12 hours, within about 8 hours, within about 5 hours,within about 4 hours, within about 3 hours, within about 2 hours, orwithin about 1 hours of administration to said patient. In someembodiments, effective amount means an amount of methylnaltrexonesufficient to achieve laxation within about 4 hours of administration tothe patient. In some embodiments, effective amount means an amount ofmethylnaltrexone sufficient to achieve laxation within about 4 hours ofadministration to the patient for at least 99%, at least 95%, at least90%, at least 85%, at least 80%, at least 75%, or at least 50% of alldoses administered. In some embodiments, effective amount means anamount of methylnaltrexone sufficient to achieve laxation within about 4hours of administration to the patient for all doses administered duringfirst four weeks of dosing.

In some embodiments, the formulations are administered to a fastedpatient. As used herein, the term “fasted” means that the patient hasnot eaten any food for at least 2 hours, at least 4 hours, for at least6 hours, for at least 8 hours, for at least 10 hours, or for at least 12hours prior to administration of a provided formulation. In certainembodiments, the term “fasted” means an overnight fast. It is believedthat improved effects will be seen in fasted patients than in fedpatients. These effects may be magnified in patients administeredmethylnatrexone in a provided tablet as compared with patientsadministered the same dose in capsule form. Thus, administration of aprovided methylnaltrexone tablet formulation to a patient in a fastedstate is believed to be advantageous.

In other embodiments, the formulations are administered to a patientthat has not fasted. Therefore, there is no requirement that the patientnot have eaten before methylnaltrexone is administered.

Combination Products and Combined Administration

It will also be appreciated that provided compositions and formulationscan be employed in combination therapies, that is, provided formulationscan be administered concurrently with, prior to, or subsequent to, oneor more other desired therapeutics or medical procedures. Particularcombination therapies (therapeutics or procedures) to employ in acombination regimen will take into account compatibility of the desiredtherapeutics and/or procedures and the desired therapeutic effect to beachieved. It will also be appreciated that therapies employed mayachieve a desired effect for the same disorder (for example, aformulation may be administered concurrently with another compound usedto treat the same disorder), or they may achieve different effects(e.g., control of any adverse effects). As used herein, additionaltherapeutic compounds which are normally administered to treat orprevent a particular disease, or condition, are known as “appropriatefor the disease, or condition, being treated.”

In some embodiments, methylnaltrexone or an ion pair or formulation ofthe invention and one or more other active agents may be administeredtogether in a single formulation (e.g., unit dosage form); in otherembodiments, methylnaltrexone and one or more other active agents may beadministered as separate formulations. In certain embodiments,methylnaltrexone and/or one or more other active agent may beadministered in multiple doses.

In some embodiments, the other active agent administered in combinationwith a methylnaltrexone ion pair or formulation of the invention is anopioid. Combination therapy of methylnaltrexone and an opioid can allowsimultaneous relief of pain and minimization of opioid-associated sideeffects (e.g., gastrointestinal effects (e.g., delayed gastric emptying,altered GI tract motility)). Accordingly and in certain embodiments, thepresent invention provides a unit dosage form comprising a combinationof methylnaltrexone with an opioid together in a single layer dosageform (e.g., tablet). In some embodiments, such a unit dosage form may bea bi-layer tablet comprising methylnaltrexone in one layer and an opioidin another layer. In a specific embodiment, the combination unit dosageform is suitable for oral administration.

Opioids useful for analgesia are known in the art. For example, opioidcompounds include, but are not limited to, alfentanil, anileridine,asimadoline, bremazocine, buprenorphine, butorphanol, codeine, dezocine,diacetylmorphine (heroin), dihydrocodeine, diphenoxylate, ethylmorphine,fedotozine, fentanyl, funaltrexamine, hydrocodone, hydromorphone,levallorphan, levomethadyl acetate, levorphanol, loperamide, meperidine(pethidine), methadone, morphine, morphine-6-glucoronide, nalbuphine,nalorphine, nicomorphine, opium, oxycodone, oxymorphone, papaveretum,pentazocine, propiram, propoxyphene, remifentanyl, sufentanil, tilidine,trimebutine, and tramadol. In some embodiments the opioid is at leastone opioid selected from alfentanil, buprenorphine, butorphanol,codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone,levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine,nicomorphine, oxycodone, oxymorphone, papaveretum, pentazocine,propiram, propoxyphene, sufentanil and/or tramadol. In certainembodiments of the present invention, the opioid is selected frommorphine, codeine, oxycodone, hydrocodone, dihydrocodeine, propoxyphene,fentanyl, tramadol, and mixtures thereof. In a particular embodiment,the opioid is loperamide. In other embodiments, the opioid is a mixedagonist such as butorphanol. In some embodiments, the subjects areadministered more than one opioid, for example, morphine and heroin ormethadone and heroin.

Typically, the amount of other active agent(s) administered incombination therapy may be no more than the amount that would normallybe administered in monotherapy with the relevant agent(s). In certainembodiments, the amount of other active agent administered incombination therapy may be less than that normally administered inmonotherapy with the relevant agent(s). For example, in certainembodiments of the present invention, the amount of additional activeagent can range from about 50% to 100% of the amount normally present ina formulation comprising that compound as the only therapeutic agent.

In certain embodiments, formulations may also be used in conjunctionwith and/or in combination with conventional therapies forgastrointestinal dysfunction to aid in the amelioration of constipationand bowel dysfunction. For example, conventional therapies include, butmay not be limited to functional stimulation of the intestinal tract,stool softening agents, laxatives (e.g., diphelymethane laxatives,cathartic laxatives, osmotic laxatives, saline laxatives), bulk formingagents and laxatives, lubricants, intravenous hydration, and nasogastricdecompression.

Uses and Kits of Compositions and Formulations

The present invention provides pharmaceutically acceptable formulationsas described herein comprising methylnaltrexone for oral administrationuseful for the delivery of such compounds in any context in which suchdelivery is desirable. In certain embodiments, provided formulations areuseful for the delivery of methylnaltrexone in antagonizing undesirableside effects of opioid analgesic therapy (e.g., gastrointestinal effects(e.g., delayed gastric emptying, altered GI tract motility)).Furthermore, formulations may be used as to treat subjects havingdisease states that are ameliorated by binding μ opioid receptors, or inany treatment wherein temporary suppression of the μ opioid receptorsystem is desired (e.g., ileus). In certain embodiments of the presentinvention, methods of use of provided formulations are in humansubjects.

Accordingly, administration of provided formulations may be advantageousfor treatment, prevention, amelioration, delay or reduction of sideeffects of opioid use, such as, for example, gastrointestinaldysfunction (e.g., inhibition of intestinal motility, constipation, GIsphincter constriction, nausea, emesis (vomiting)), biliary spasm,opioid bowel dysfunction, colic, dysphoria, pruritis, urinary retention,depression of respiration, papillary constriction, cardiovasculareffects, chest wall rigidity and cough suppression, depression of stressresponse, and immune suppression associated with use of narcoticanalgesia, or combinations thereof. Use of a formulation may thus bebeneficial from a quality of life standpoint for subjects undergoing useof opioids, as well as to reduce complications arising from chronicconstipation, such as hemorrhoids, appetite suppression, mucosalbreakdown, sepsis, colon cancer risk, and myocardial infarction.

In some embodiments, provided formulations are useful for administrationto a subject undergoing acute opioid use. In some embodiments, providedformulations are useful for administration to patients suffering frompost-operative gastrointestinal dysfunction.

In certain embodiments, provided formulations are also useful foradministration to subjects undergoing chronic opioid use (e.g.,terminally ill patients receiving opioid therapy such as an AIDSpatient, a cancer patient, a cardiovascular patient; subjects receivingchronic opioid therapy for pain management; subjects undergoing opioidtherapy for maintenance of opioid withdrawal). In some embodiments, thesubject is a subject using opioid therapy for chronic pain management.In certain embodiments, the pain is non-malignant pain (e.g., back pain,neuropathic pain, pain associated with fibromyalgia, osteoarthritis). Insome embodiments, the subject is a terminally ill patient. In otherembodiments the subject is a person undergoing opioid withdrawalmaintenance therapy.

In certain embodiments, the formulations provided herein areadministered to subjects that have been selected for treatment withmethylnaltrexone. In specific embodiments, the subject is selected basedon the subject having an increased risk for developing one or more ofthe conditions set forth above. In another embodiment, the subject isselected based on the use of opioid therapy for pain management, orbased on having one or more of the conditions set forth herein. Incertain embodiments, the subject is constipated or has a history ofconstipation due to opioid therapy. In one embodiment, a constipatedsubject has not had a bowel movement in the previous three days. In oneembodiment, a constipated subject has had less than three bowelmovements in the previous week. In certain embodiments, a constipatedsubject has had less than three rescue-free bowel movements per week onaverage over the last four consecutive weeks, and one or more of thefollowing: (a) hard or lumpy stools, (b) straining during bowelmovements, and/or (c) sensation of incomplete evacuation after bowelmovements.

In certain embodiments, the subject is selected for treatment with amethylnaltrexone formulation described herein based on the use ofopioids, e.g., for non-malignant pain. The subject may be using opioidsintermittently or regularly. In one embodiment, the subject that isselected has been taking opioids as needed. In one embodiment, thesubject that is selected has been taking opioids for less than one week.In one embodiment, the subject that is selected has been taking opioidsover the course of at least one week. In another embodiment, the subjectthat is selected has been taking opioids over the course of at least twoweeks. In another embodiment, the subject that is selected has beentaking opioids over the course of at least three weeks. In anotherembodiment, the subject that is selected has been taking opioids overthe course of at least four weeks. In another embodiment, the subjectthat is selected has been taking opioids over the course of at leastthree months. In another embodiment, the subject that is selected hasbeen taking opioids over the course of at least six months. In anotherembodiment, the subject that is selected has been taking opioids overthe course of at least twelve months. In another embodiment, the subjectthat is selected has been taking opioids over the course of more thanone year. In another embodiment, the subject that is selected has beentaking opioids at least every other day over the course of at least twoweeks. In one embodiment, the subject that is selected has beenreceiving at least 7 doses >25 mg of oral morphine equivalents over atleast 14 days. In one embodiment, the subject that is selected has beenreceiving a daily dose of >50 mg of oral morphine equivalents for atleast 14 days. In one embodiment, the subject that is selected isconstipated due to opioid therapy and has been receiving a daily doseof >50 mg of oral morphine equivalents for at least 14 days. In certainembodiments, the subject has been receiving a daily dose of >50 mg oforal morphine equivalents for at least 14 days; and has had less thanthree (3) rescue-free bowel movements per week on average over the leastfour consecutive weeks that were associated with one or more of thefollowing: (a) a Bristol Stool Form Scale type 1 or 2 for at least 25%of the rescue-free bowel movements, (b) straining during at least 25% ofthe rescue-free bowel movements; and/or (c) a sensation of incompleteevacuation after at least 25% of the rescue-free bowel movements. Arescue-free bowel movement refers to a bowel movement associated with nolaxative use within the 24 hours prior to the bowel movement.

In certain embodiments, the subject selected for treatment with amethylnaltrexone formulation described herein is a subject sufferingfrom opioid-induced constipation. In certain embodiments, the subjectselected for treatment with a methylnaltrexone formulation describedherein is a subject with advanced illness who is receiving palliativecare and is suffering from opioid-induced constipation. In certainembodiments, the subject selected for treatment with a methylnaltrexoneformulation described herein is a subject with advanced illness who isreceiving palliative care and is suffering from opioid-inducedconstipation where response to laxative therapy (e.g., bisacodyl,senokot, docusate) has not been sufficient. In certain embodiments, thesubject selected for treatment with a methylnaltrexone formulationdescribed herein is a subject with non-malignant pain who is sufferingfrom opioid-induced constipation. In certain embodiments, the subjectselected for treatment with a methylnaltrexone formulation describedherein is a subject with non-malignant pain who is suffering fromopioid-induced constipation where response to laxative therapy (e.g.,bisacodyl, senokot, docusate) has not been sufficient. In certainembodiments, the subject selected for treatment with a methylnaltrexoneformulation described herein has not responded to standard laxativetherapy. In certain embodiments, the subject selected for treatment witha methylnaltrexone formulation described herein has responded tostandard laxative therapy. In certain embodiments, the subject selectedfor treatment with a methylnaltrexone formulation described herein isconcurrently administered laxative therapy.

Alternative or additional uses for provided formulations describedherein are useful for treating effects of opioid use including, e.g.,aberrant migration or proliferation of endothelial cells (e.g., vascularendothelial cells), increased angiogenesis, and increase in lethalfactor production from opportunistic infectious agents (e.g.,Pseudomonas aeruginosa). Additional advantageous uses of providedformulations include treatment of opioid-induced immune suppression,inhibition of angiogenesis, inhibition of vascular proliferation,treatment of pain, treatment of inflammatory conditions such asinflammatory bowel syndrome, treatment of infectious diseases anddiseases of the musculoskeletal system such as osteoporosis, arthritis,osteitis, periostitis, myopathies, and treatment of autoimmune diseases.

In certain embodiments, provided formulations may be used in methods forpreventing, inhibiting, reducing, delaying, diminishing or treatinggastrointestinal dysfunction, including, but not limited to, irritablebowel syndrome, opioid-induced bowel dysfunction, colitis,post-operative or postpartum ileus, nausea and/or vomiting, decreasedgastric motility and emptying, inhibition of the stomach, and smalland/or large intestinal propulsion, increased amplitude ofnon-propulsive segmental contractions, constriction of sphincter ofOddi, increased anal sphincter tone, impaired reflex relaxation withrectal distention, diminished gastric, biliary, pancreatic or intestinalsecretions, increased absorption of water from bowel contents,gastro-esophageal reflux, gastroparesis, cramping, bloating, abdominalor epigastric pain and discomfort, constipation, idiopathicconstipation, post-operative gastrointestinal dysfunction followingabdominal surgery (e.g., colectomy (e.g., right hemicolectomy, lefthemicolectomy, transverse hemicolectomy, colectomy takedown, lowanterior resection), hysterectomy), and delayed absorption of orallyadministered medications or nutritive substances.

Provided formulations are also useful in treatment of conditionsincluding cancers involving angiogenesis, immune suppression, sicklecell anemia, vascular wounds, and retinopathy, treatment of inflammationassociated disorders (e.g., irritable bowel syndrome), immunesuppression, chronic inflammation.

In other embodiments, provided formulations and unit dose forms areuseful in preparation of medicaments, including, but not limited tomedicaments useful in the treatment of side effects of opioid use,including gastrointestinal side effects (e.g., inhibition of intestinalmotility, GI sphincter constriction, constipation), nausea, emesis,vomiting, dysphoria, pruritis, or a combination thereof. Providedformulations are useful for preparations of medicaments, useful intreatment of patients receiving acute opioid therapy (e.g., patientssuffering from post-operative gastrointestinal dysfunction receivingacute opioid administration) or subjects using opioids chronically(e.g., terminally ill patients receiving opioid therapy such as an AIDSpatient, a cancer patient, a patient with cardiovascular disease;subjects receiving chronic opioid therapy for pain management (malignantor non-malignant pain); or subjects undergoing opioid therapy formaintenance of opioid withdrawal). Still further, preparation ofmedicaments useful in the treatment of pain, treatment of inflammatoryconditions such as inflammatory bowel syndrome, treatment of infectiousdiseases, treatment of diseases of the musculoskeletal system such asosteoporosis, arthritis, osteitis, periostitis, myopathies, treatment ofautoimmune diseases and immune suppression, therapy of post-operativegastrointestinal dysfunction following abdominal surgery (e.g.,colectomy (e.g., right hemicolectomy, left hemicolectomy, transversehemicolectomy, colectomy takedown, low anterior resection), idiopathicconstipation, and ileus (e.g., post operative ileus, post partum ileus),and treatment of disorders such as cancers involving angiogenesis,chronic inflammation and/or chronic pain, sickle cell anemia, vascularwounds, and retinopathy.

In still further embodiments, veterinary applications (e.g., treatmentof domestic animals, e.g., horse, dogs, cats) of use of providedformulations are provided. Thus, use of provided formulations inveterinary applications analogous to those discussed above for humansubjects is contemplated. For example, inhibition of equinegastrointestinal motility, such as colic and constipation, may be fatalto a horse. Resulting pain suffered by the horse with colic can resultin a death-inducing shock, while a long-term case of constipation mayalso cause a horse's death. Treatment of equines with peripheral opioidreceptor antagonists has been described, e.g., in U.S. PatentPublication No. 2005/0124657, published Jan. 20, 2005, which isincorporated herein by reference.

Still further encompassed by the invention are pharmaceutical packsand/or kits comprising formulations described herein, and a container(e.g., a foil or plastic package, or other suitable container).Optionally instructions for use are additionally provided in such kits.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

All features of each of the aspects of the invention apply to all otheraspects mutatis mutandis. The contents of all references, patents,pending patent applications and published patents, cited throughout thisapplication are hereby expressly incorporated by reference.

EXAMPLES Example 1

Methylnaltrexone bromide may be prepared according to the methodsdescribed in detail in international PCT Patent Application publicationnumber, WO 2006/127899, or obtained from commercial sources such asCovidien, Saint Louis, Mo. Formulations containing methylnaltrexone wereprepared using pharmaceutically acceptable excipients. Spheroidscontaining methylnaltrexone were prepared. Capsules were prepared byfilling capsules with spheroids. Some capsules were prepared to containenterically coated spheroids, which spheroids dissolve only afterpassing through the stomach. The capsules, without an enteric coat, orafter dissolution of the enteric coat, will dissolve over 10-30 minutes.Tablets also were prepared from spheroids, using conventionaltechniques. The tablets dissolve in under 10 minutes.

The spheroids were prepared by a wet granulation process followed byextrusion and spheronization, as described in the following generalmethod. Methylnaltrexone bromide and pharmaceutically acceptableexcipients were combined in an aqueous solution. Water was added untilwet mass suitable for extrusion was obtained. The wet mass was passedthrough an extruder, and the extrudate was spheronized in a spheronizer.The resulting spheroids were dried in a fluid bed drier and passedthrough a screen. The uncoated spheroids were stored in appropriatecontainer.

Example 2 Administration of Capsules Containing Enterically CoatedMethylnaltrexone Spheroids

Capsules containing enterically coated spheroids of methylnaltrexone asdescribed in Example 1 were tested in patients suffering fromopioid-induced constipation. The patients in this study were not chronicmethadone maintenance patients. The patients had chronic non-malignant(not cancer) pain where the non-malignant condition underlying thechronic pain (e.g., osteoarthritis, back pain, neuropathic pain) had adocumented history of at least 2 months before screening, stable painfor at least 1 month. The patients were on opioids for at least onemonth and at a daily dose of greater than or equal to 20 mg of morphineequivalents per day for at least two weeks before the screening visitand during the screening visit period with no anticipated changes duringthe study. The patients also had a history of constipation due to opioiduse for at least one month before the screening visit. Constipationdefined as less than 3 bowel movements per week on average and 1 or moreof the following: (i) hard or lumpy stools for at least 25% of bowelmovements, (ii) a sensation of incomplete evacuation following at least25% of bowel movements, (iii) straining during at least 25% of bowelmovements.

Patients were administered enterically coated methylnaltrexone capsulescontaining 10 mg, 50 mg, 150 mg, 300 mg or 450 mg of methylnaltrexone.The average peak plasma level of methylnaltrexone resulting from thedoses was as follows: (i) for 10 mg, less than 1 ng/ml, (ii) for 50 mg,less than 5 ng/ml, (iii) for 150 mg, less than 5 ng/ml, (iv) for 300 mg,less than 10 ng/mL, and (v) for 450 mg, less than 20 ng/mL. Thesecapsules containing enterically coated preparations of methylnaltrexonewere not effective for treating opioid-induced constipation. They didnot induce laxation and did not cause more bowel movements in patientsrelative to controls.

Example 3 Administration of Capsules Containing Methylnaltrexone notEnterically Coated

Capsules containing spheroids of methylnaltrexone, but without theenteric coating, prepared as described in Example 1, were tested inpatients receiving opioids for non-malignant pain. The patients in thisstudy were not chronic methadone maintenance patients. The patients wereselected on the basis of the same criteria as the criteria used inExample 2, except the minimum daily dose of opioids was equal to orgreater than 30 mg, instead of 20 mg of morphine equivalents. Doses of150 mg, 300 mg, 450 mg, and 600 mg were tested. These doses resulted inaverage peak plasma levels of between about 15 and 40 ng/ml, on theorder of 3 or more times lower than the average peak plasma levelsassociated with effective doses of subcutaneous methylnaltrexoneinjection. These capsules containing spheroids without the entericcoating did not induce laxation and did not cause more bowel movementsin this patient population relative to controls.

Administration of Tablets Containing Methylnaltrexone not EntericallyCoated

Tablets containing spheroids of methylnaltrexone, without an entericcoating, prepared as described in Example 1, were tested in patientsreceiving opioids for non-malignant pain. The patients in this studywere not chronic methadone maintenance patients. The patients wereselected on the basis of the same criteria as the criteria used inExample 3. Doses of 150 mg, 300 mg, 450 mg, and 600 mg were tested.These doses resulted in average peak plasma levels of between about 7and 40 ng/ml. These tablets without an enteric coating showedstatistically significant activity at one dose, but did not consistentlyinduce laxation across all doses.

Both tablets and capsules containing uncoated spheroids had similarcompositions except that spheroids were compressed with pharmaceuticallyacceptable excipients to form tablets, while spheroids were encapsulatedinto hard gelatine shells to prepare capsules. Once contacted with anaqueous medium, the tablets disintegrated immediately and almost all thedrug dissolved in less than 10 minutes. In contrast, it took 10 minutesfor the capsule shells to dissolve and at least 30 minutes for thecomplete dissolution of the drug from the capsules. (FIG. 1) Plasmalevels associated with both dosage forms containing uncoated spheroidswere variable (tablets produced more consistent average peak plasmalevels relative to the capsule) and overlapping among the subjects.

Example 4 Determination of Partition Coefficient

Ion pairs of methylnaltrexone with amphiphilic pharmaceuticallyacceptable excipients were prepared and the apparent octanol-waterpartition coefficient (APC) was measured and compared to that ofmethylnaltrexone bromide. A pre-determined amount of each of MNTX-heptylsulfate and MNTX-dodecyl sulfate was dissolved in 2 mL of 1-octanol thatwas saturated with water. Two mL of water that was saturated with1-octanol was added to each MNTX salt solution. The mixtures were shakenovernight at room temperature, and 1 mL of the 1-octanol phase was thendiluted to 10 mL with the mobile phase used for chromatographic (HPLC)analysis of the samples. And 1 mL of the aqueous phase was diluted to 5mL with the mobile phase. The samples were then analyzed by HPLC todetermine the apparent partition coefficient and log P for each MTNXsalt. The pH of the aqueous phases for each of the salts was between 4.5and 6.8. (The reported partition coefficient for MNTX is 0.025 and theLog P is −1.605.)

MNTX Salt mg used APC Log P MNTX-heptyl sulfate 21.323 1.961 0.292MNTX-dodecyl sulfate 15.175 32.014 1.505 MNTX-laurate 12.843 2.131 0.328

Example 5 Preparation of Tablets Containing Methylnaltrexone Bromide andSodium Dodecyl Sulfate

The present Example describes the preparation of tablets containingmethylnaltrexone, sodium dodecyl sulfate (SDS), and an effervescentdisintegrant (sodium bicarbonate). The quantitative formulation ofmethylnaltrexone (150 mg) tablets is provided in Table 5-1.

TABLE 5-1 Composition of Methylnaltrexone Bromide 150 mg UncoatedTablets with SDS Unit Dose Ingredient % w/w mg/Tablet GranulationMethylnaltrexone Bromide^(a) 28.95 150.00 Microcrystalline Cellulose11.30 58.54 Sodium Dodecyl Sulfate 9.65 50.00 Crospovidone 1.83 9.48Polysorbate 80 (vegetable grade) 2.07 10.73 Edetate Calcium Disodium0.28 1.46 Dihydrate Purified Water^(b) NA 40.03 Blend SilicifiedMicrocrystalline 28.95 150.00 Cellulose Crospovidone 3.00 15.52 SodiumBicarbonate 11.30 58.54 Talc 1.93 10.00 Colloidal Silicon Dioxide 0.492.50 Final Blend Magnesium Stearate 0.25 1.28 Total 100.0% 518.05 mg^(a)Based upon 100% purity “as is”, quantity may be adjusted based onactual potency, with corresponding adjustments made to microcrystallinecellulose. ^(b)Removed by drying. Does not appear in final dosage form.Method of Manufacture and Packaging: Procedure

1. Blend methylnaltrexone bromide, microcrystalline cellulose, sodiumdodecyl sulfate (SDS), and crospovidone in a granulator.

2. Make a solution containing edetate calcium disodium and polysorbate80 in purified water.

3. While mixing blend from Step 1, add the edetate calciumdisodium/polysorbate 80 solution for approximately 4 minutes. Additionalwater might be added to obtain proper granulation. Note: the granulationsteps may be completed in sub-batches to obtain larger batch sizes.

4. Dry the granulation.

5. Using suitable mill, mill the granulation from #4.

6. Add material from #5 to a suitable blender.

7. Record the yield for milling and adjust the levels of excipients forthe final blend.

8. Optional screening of crospovidone, silicified microcrystallinecellulose, sodium bicarbonate, talc, silicon dioxide, and magnesiumstearate through appropriate sieve.

9. Add to the blender, crospovidone, sodium bicarbonate, talc, andsilicified microcrystalline cellulose, and blend

10. Optionally screening the blend of Step 9 through appropriate sieveand add to the blender and blend.

11. Optionally, take a portion of the blend, add to the silicon dioxideand bag blend.

12. Optionally, transfer the pre-mix of the silicon dioxide and add tothe blender and blend.

13. Take a portion of the blend, add to the magnesium stearate and bagblend. Note: Step 13 may not be required for batches larger than 50 kg.

14. Transfer the pre-mix magnesium stearate and blend to the blender andblend.

15. Record the final yield of blend.

16. Compress the final blend from step 15 using a suitable compressionmachine fitted with tooling which can produce tablets of the requiredspecification.

17. Weigh the yield of acceptable tablets.

Example 6

Tablets including methylnaltrexone bromide (150 mg), sodium dodecylsulfate (SDS), and sodium bicarbonate were manufactured using the methoddescribed in Example 5. The tablet was placed in a dissolution apparatuswith paddles at 100 rpm in 900 mL of 0.1 N HCl at 37° C. Samples werethen removed at specified times points and analyzed by HPLC. Thedissolution rates of two tablets were determined. The dissolutionprofile of the SDS tablet with sodium bicarbonate is shown in FIG. 2.Greater than 90% of the methylnaltrexone from the tablets was dissolvedwithin 11 minutes.

Example 7 Administration of Provided Formulations in GI-PhysiologyAltered Dogs

Oral bioavailability and pharmacokinetic profiles of tablets containingmethylnatraxone bromide (150 mg), sodium dodecyl sulphate (SDS) andsodium bicarbonate, prepared as described in Example 5, were comparedwith tablets containing uncoated spheroids of methylnaltrexone, but notcontaining an amphiphilic pharmaceutically acceptable carrier or aneffervescent disintegrant, prepared as described in Example 1. UsingGI-physiology altered male beagle dogs, atropine (˜20 μg/kg; IV) andpentagastrin (˜10 μg/kg; 1M) were administered 15 minutes prior toformulation administration and another dose of pentagastrin (10 μg/kg;1M) was administered 30 minutes post dose. Atropine slows down canine GImotility and pentagastrin decreases pH resulting in GI conditions almostsimilar to that of humans. The formulations (150 mg MNTX) were dosed tosix dogs (9.4-13.7 kg) via oral administration following an overnightfast and blood samples were drawn at 0 (predose), 0.5, 1, 2, 3, 4, 6, 8,12, 24, and 48 hours after dosing; plasma was separated and assayed formethylnaltrexone content.

Individual dog plasma methylnaltrexone concentration-time profiles weresubjected to non-compartmental pharmacokinetic analyses (WinNonlin,Model 200). The results are summarized in Table 7-1 below.

TABLE 7-1 Individual and Mean (±SD) MNTX Pharmacokinetic Parameters inGI Physiology Regulated Dogs Following a Single Oral Administration of150 mg MNTX Prototype Formulations Dose C_(max) AUC_(0-∞) FormulationDog (mg/kg) (ng/mL) (hr * ng/mL) Tablet no SDS Mean 15.2 ± 565 ± 2091 ±SD 0.46 206 572 Tablet with SDS Mean 15.7 ± 978 ± 2983 ± SD 0.91 322 720

As summarized in the above Table 7-1, oral administration of prototypetablet formulation containing the ion-pairing agent sodium dodecyl(lauryl) sulfate resulted in qualitatively greater methylnaltrexonesystemic exposures than tablets containing no ion pairing agent.

Example 8

This example reports on the efficacy of methylnaltrexone in the SDStablet formulation at a dose of 300 and 450 mg administered orally tosubjects with chronic non-malignant pain. Subjects enrolled in thisstudy had to have a history of constipation due to opioid use for atleast one month before the screening visit. The study was a phase 1,open-label, single dose, inpatient studies. Subjects receivedmethylnaltrexone as a single dose (2×150 mg or 3×150 mg) of the SLStablet formulation after an overnight fast of at least 10 hours. Thedose was taken orally with 240 mL of room temperature water atapproximately 0800 hours on day 1. Opioid medication was provided atapproximately the same time every day. Each subject participated in thestudy for approximately 3 weeks. This included a screening evaluationwithin 3 weeks before test article administration and a 2 day/1 nightinpatient period.

The results are presented in FIG. 3. This figures shows a plot of thecomparison between time and the percentage of patients having a firstlaxation response in patients with chronic malignant pain administered amethylnaltrexone (300 mg and 450 mg) SDS tablet after a 10 hour fast.The SLS tablet formulation resulted in increases in percentage laxationwithin 4 hours and within 24 hours in subject patients.

In Example 8, the percentage of patients who laxated within 4 hours ofreceiving a single initial dose of 450 mg of the SDS formulation of theinvention was approximately 41%. In Example 8, the percentage ofpatients who laxated within 24 hours of receiving a single initial doseof 450 mg of the SDS formulation of the invention was approximately 72%.

The foregoing study was not designed to establish statisticalsignificance of laxation. There was no placebo group. It is noted thathistorically in larger studies of chronic nonmalignant pain patientsdesigned with similar but more rigorous inclusion/exclusion criteria,the percentage of subjects receiving placebo who laxated within 4 hourswas on the order of about 9%-13%. One of skill in the art willappreciate that the placebo response in the present study could bedifferent from the previous studies due to such factors as the smallerstudy size and different inclusion/exclusion criteria. Without wishingto be bound by any theory of the invention, it is believed that theremay be a dual mechanism involved in achieving laxation when an oral doseis administered and that the plasma levels required to achieve laxationwhen dosing orally may be less than those required when dosingsubcutaneously.

One skilled in the art will readily ascertain the essentialcharacteristics of the invention and understand that the foregoingdescription and Examples are illustrative of practicing the providedinvention. Those skilled in the art will be able to ascertain using nomore than routine experimentation, many variations of the detailpresented herein may be made to the specific embodiments of theinvention described herein without departing from the spirit and scopeof the present invention.

What is claimed is:
 1. A pharmaceutical composition for oraladministration comprising a solid dosage of (i) methylnaltrexone, or apharmaceutically acceptable salt thereof, and (ii) and an amphiphilicpharmaceutically acceptable excipient comprising a saturated orunsaturated, branched or unbranched, cyclic or acyclic C₄₋₃₀ aliphaticgroup that is optionally substituted, wherein when the methylnaltrexone,or the pharmaceutically acceptable salt thereof, and the amphiphilicpharmaceutically acceptable excipient are in solution, the apparentoctanol/water partition coefficient for methylnaltrexone is at least0.25 at a pH between 1 and
 4. 2. The pharmaceutical compositionaccording to claim 1, wherein the amphiphilic pharmaceuticallyacceptable excipient has a pK_(a) of 3 or less.
 3. The pharmaceuticalcomposition according to claim 1, wherein the amphiphilicpharmaceutically acceptable excipient comprises a sulfate (−OSO₃ ⁻)group.
 4. The pharmaceutical composition according to claim 1, whereinthe amphiphilic pharmaceutically acceptable excipient comprises anacyclic C₄₋₃₀ aliphatic group that is optionally substituted.
 5. Thepharmaceutical composition according to claim 1, wherein the amphiphilicpharmaceutically acceptable excipient comprises a saturated, unbranched,acyclic, unsubstituted C₄₋₃₀ alkyl group.
 6. The pharmaceuticalcomposition according to claim 1, wherein the amphiphilicpharmaceutically acceptable excipient comprises a saturated, unbranched,acyclic, unsubstituted C₇₋₁₅ alkyl group.
 7. The pharmaceuticalcomposition according to claim 1, wherein the amphiphilicpharmaceutically acceptable excipient comprises a C₁₂ n-alkyl group. 8.The pharmaceutical composition according to claim 1, wherein theamphiphilic pharmaceutically acceptable excipient is sodium dodecylsulfate (SDS).
 9. The pharmaceutical composition of claim 1, furthercomprising a disintegrant.
 10. The pharmaceutical composition of claim9, wherein at least 50% of the composition dissolves in a dissolutionapparatus with paddles at 100 rpm in 900 mL of 0.1 N HCl at 37° C.within about 15 minutes.
 11. The composition of claim 10, wherein atleast 75% of the composition dissolves in a dissolution apparatus withpaddles at 100 rpm in 900 mL of 0.1 N HCl at 37° C. within about 15minutes.
 12. The composition according to claim 1, wherein the apparentoctanol/water partition coefficient is at least
 1. 13. The compositionaccording to claim 12, wherein the apparent octanol/water partitioncoefficient is at least
 10. 14. The composition according to claim 13,wherein the apparent octanol/water partition coefficient is at least 20.15. The composition according to claim 1, wherein the amphiphilicpharmaceutically acceptable excipient is an anionic surfactant.
 16. Thecomposition according to claim 9, wherein the disintegrant is aneffervescent disintegrant.
 17. The composition according to claim 16,wherein the disintegrant is a bicarbonate.
 18. The composition accordingto claim 1, wherein the composition is a tablet.
 19. The compositionaccording to claim 1, wherein the composition is a tablet comprising atleast one or more of a binder, a chelating agent, a wetting agent, alubricant, a non-functional coating, or an antioxidant, and combinationsthereof.
 20. The composition according to claim 19, wherein thecomposition comprises a chelating agent.
 21. The composition accordingto claim 20, wherein the chelating agent is a salt of EDTA.
 22. Thecomposition according to claim 21, wherein the chelating agent iscalcium EDTA disodium.
 23. The composition according to claim 19,wherein the composition comprises a lubricant.
 24. The compositionaccording to claim 23, wherein the lubricant is magnesium stearate. 25.The composition according to claim 24, wherein the composition comprisesan antioxidant.
 26. The composition according to claim 25, wherein theantioxidant is ascorbic acid.
 27. The composition according to claim 19,wherein the antioxidant is ascorbic acid.
 28. A pharmaceuticalcomposition for oral administration comprising a solid dosage of acompound of formula (I):

wherein A⁻ is an anion of the amphiphilic pharmaceutically acceptableexcipient comprising a saturated or unsaturated, branched or unbranched,cyclic or acyclic C₄₋₃₀ aliphatic group that is optionally substituted,wherein when the compound of formula I is in solution, the apparentoctanol/water partition coefficient is at least 0.25 at a pH between 1and
 4. 29. The pharmaceutical composition of claim 1, wherein themethylnaltrexone, or a pharmaceutically acceptable salt thereof, and theamphiphilic pharmaceutically acceptable excipient form an ion pair whendissolved in solution.
 30. The pharmaceutical composition of claim 1,wherein the composition comprises from about 5% to about 80% amphiphilicpharmaceutically acceptable excipient, based upon the total weight ofthe composition.
 31. The pharmaceutical composition of claim 1, whereinthe composition comprises about 7% to about 75% methylnaltrexone, basedupon total weight of the composition.
 32. The composition according toclaim 1, wherein the apparent octanol/water partition coefficient is atleast
 30. 33. The composition according to claim 16, wherein thedisintegrant is sodium bicarbonate.
 34. The composition according toclaim 19, wherein the composition comprises: (a) about 7% to about 75%of methylnaltrexone bromide, based upon total weight of the composition;(b) about 5% to about 80% of the amphiphilic pharmaceutically acceptableexcipient, based upon total weight of the composition; (c) about 0.01%to about 5% of a chelating agent, based upon total weight of thecomposition; (d) about 1% to about 25% of a wetting agent, based upontotal weight of the composition; (e) about 5% to about 90% of a binder,based upon total weight of the composition; (f) about 1% to about 25% ofa disintegrant, based upon total weight of the composition; (g) about0.1% to about 7% of a lubricant, based upon total weight of thecomposition; and optionally (h) about 0.01% to about 5% of anantioxidant, based upon the total weight of the composition.
 35. Thecomposition according to claim 34, wherein the binder comprisesmicrocrystalline cellulose and silicified microcrystalline cellulose.36. The composition according to claim 34, wherein the disintegrant iscrospovidone.
 37. The composition according to claim 34, wherein thechelating agent is calcium EDTA.
 38. The composition according to claim34, wherein the wetting agent is polysorbate
 80. 39. The compositionaccording to claim 34, wherein the lubricant is magnesium stearate. 40.The composition according to claim 34, wherein the antioxidant isascorbic acid.